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CAS No. : | 6908-41-4 | MDL No. : | MFCD00009984 |
Formula : | C9H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VBWFYEFYHJRJER-UHFFFAOYSA-N |
M.W : | 166.17 | Pubchem ID : | 81325 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With (carbonyl)chloro(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In tert-Amyl alcohol at 130℃; for 20 h; Inert atmosphere; Cooling | Example 6Direct Single-Stage Amination of Alcohols andHydroxy Acids by Means of Ammonia Over aHomogeneous Ruthenium Catalyst and Xantphos ata high V7J Vgas (according to the invention)Under an argon atmosphere, m g of starting material, mRU g of [carbonylchlorohydridotris(triphenylphosphane)ruthenium(II)] and mp g of 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene as catalyst and V07 ml of 2-methyl-2-butanol as solvent were introduced into a 50 mlsteel tube. The vessel was closed, pressurized three times with 20 bar of argon and depressurized each time. The vessel was then cooled by means of dry ice and m g of ammonia were condensed in. The reactor is heated to T° C. and maintained at this temperature for 20 hours. Afier cooling to room temperature, the reactor was depressurized and opened, the solvent was removed on a rotary evaporator and the residue was dissolved in methanol and then analysed by gas chromatography. Reaction parameters and conversions and selectivities to the desired reaction product are shown in Tab. 5. The results show that many different hydroxy-thnctionalized substrates can be aminated by the method described. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tert.-butylhydroperoxide; water In acetonitrile at 120℃; for 24 h; Sealed tube | General procedure: The mixture of azobenzenes 1 (0.25 mmol), alcohols 2(0.5 mmol), TBHP (1 mmol) and CH3CN (1 mL) were added into a sealed tube under air. After being stirred vigorously at 120 °C for 24 h, the mixture was evaporated under vacuum. The corresponding product was isolated by silica gel column chromatography with a petroleum ether/ethyl acetate mixture as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 15 h; Stage #2: With 18-crown-6 ether In acetonitrile at 20℃; for 40 h; |
Methyl 4-hydroxymethylbenzoate (1.00 g) was dissolved in dichloromethane (20 ml). After addition of triethylamine (0.9 ml) to the resulting solution, a dichloromethane solution (dichloromethane: 5 ml) of methanesulfonyl chloride (0.70 g) was added under ice cooling. After stirring at room temperature for 15 hours, the reaction mixture was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in acetonitrile (12 ml). Potassium cyanide (0.80 g) and 18-crown-6 (0.16 g) were added and the resulting mixture was stirred at room temperature for 40 hours. After concentration of the reaction mixture under reduced pressure, the residue was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (dichloromethane) on a silica gel column, whereby colorless crystals (0.91 g, 86percent) were obtained. A portion of the crystals were recrystallized from a mixed solvent of hexane and ethyl acetate to yield colorless crystals.1H-NMR (CDCl3) δ: 3.82(2H,s), 3.93(3H,s), 7.42(2H,d,J=8.3Hz), 8.06(2H,d,J=8.3Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(electrochemical reduction); | ||
With phenoxy [tris((2-(diphenylphosphino)ethyl)amino)hydridoruthenium monocarbonyl]; hydrogen; phenol In methanol; toluene at 130℃; for 18h; Inert atmosphere; Glovebox; Schlenk technique; | ||
Ca. 85 %Spectr. | With methanol; [tris((2-(diphenylphosphino)ethyl)amino)hydridoruthenium monocarbonyl] benzoate; hydrogen In toluene for 19h; Glovebox; Inert atmosphere; Heating; Autoclave; | II.II.9 II.9 Hydrogenation of Esters (Dimethyl terephthalate) catalyzed by [Ru(L)CO(H)]+PhCOO with methanol as activator In a dry argon filled glove box, a ca. 80 mL Premex stainless steel autocalve fitted with a PTFE inner chamber and a PTFE coated magnetic stirring bar was charged with the complex [Ru(L)CO(H)]+PhCOO~ (0.015 mmol), dimethyl terephthalate (1.0 mmol) and toluene (6 mL). Methanol was added (0.1 mL) and the autoclave was sealed. The argon atmosphere in the au- toclave was replaced with H2 by twice pressurization to 30 bar, and pressure release at room temperature. The autoclave was then pressurized with H2 gas (60 bar). The solution was heated at 130 °C (heating mantel temperature) with stirring for 19 hrs. After cooling to 0 °C, the system was vented carefully and purged for 1 minute with argon. The conversion of starting material was analyzed by GC-MS, using an Agilent Technologies 6890N gas chromatography system coupled with an Agilent Technologies 5975B mass spectrometer and equipped with an Agilent Technologies HP-5MS capillary column (30 m x 0.250 mm / 0.25 pm). By % area, ca. 85 % NP1 was obtained, with LT 5 % BDM, and then rest unreacted DMT. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With carbon tetrabromide; triphenylphosphine In benzene at 0℃; for 2h; | |
90% | With phosphorus tribromide In benzene at 0 - 20℃; | |
87% | With phosphorous pentoxide; potassium bromide In acetonitrile at 20℃; for 0.5h; | General procedure for the bromination of alcohols using KBr/P2O5 General procedure: To a mixture of alcohol (1 mmol) and KBr (1.5 mmol, 0.18 g) in acetonitrile (5 mL), P2O5 (1.5 mmol, 0.23 g) was added and the reaction was stirred at room temperature for the time specified in Table 3. After reaction completion (TLC or GC), the reaction mixture was filtered and the residue washed with ethyl acetate (3 × 8 mL). The combined organic layers were washed with water (10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to afford the corresponding product. If necessary, further purification was performed by column chromatography. |
86% | With phosphorus tribromide In benzene for 2h; Ambient temperature; | |
78% | With carbon tetrabromide; triphenylphosphine In benzene at 0℃; for 2h; | 10-12.1 (Step 1) Preparation of methyl 4- (bromomethyl) benzoate (Compound 72-a) After dissolving methyl 4- (hydroxymethyl) benzoate (1.0 g, 6.0 mmol) in benzene (40 mL), the mixture was cooled to 0 ° C and triphenylphosphine (3.2 g, 12.0 mmol) Tetrabromocarbon (4.0 g, 12.0 mmol) was added sequentially and stirred for 2 hours. After completion of the reaction, n-hexane (60 mL) was added and stirred to remove insoluble matters. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) To give the title compound 72-a (1.07 g, 78%) as a white solid |
With phosphorus tribromide | ||
With phosphorus tribromide In dichloromethane at 0℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With air In toluene at 20℃; for 24h; Irradiation; | |
99% | With 4-dimethylaminopyridine; copper(I) tetrakis(acetonitrile) hexafluorophosphate; N,N'-di-tert-butylethylenediamine; oxygen In dichloromethane at 20℃; for 3h; Schlenk technique; Molecular sieve; Sealed tube; | |
99% | With sulfur(VI) fluoride; potassium carbonate; dimethyl sulfoxide at 20℃; for 12h; chemoselective reaction; |
98% | With iodic acid In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere; | 4.1.10 4.1.1 Typical experimental procedure with HIO3 (Method A) General procedure: To a solution of p-bromobenzyl alcohol I-1 (187 mg, 1.0 mmol) in DMF (2.0 mL) was added HIO3 (194 mg, 1.1 mmol). The mixture was stirred at 60 °C for 2 h under an Ar atmosphere. After the reaction, the reaction mixture was poured into aq Na2S2O3, and extracted with a mixture of Et2O: hexane=1:1 (3*10 mL). The organic layer was dried over Na2SO4. After being filtration and removal of the solvent under reduced pressure, the residue was purified by flash short column chromatography on silica gel (EtOAc-hexane, 1:4) to give p-bromobenzaldehyde II-1 in 95% yield. |
97% | With hydrogenchloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; NaNO2 In dichloromethane; lithium hydroxide monohydrate at 20℃; for 12h; in air; | |
97% | With dihydrogen peroxide In lithium hydroxide monohydrate at 100℃; for 6h; chemoselective reaction; | |
97% | With tert.-butylhydroperoxide In toluene at 120℃; for 4h; | |
97% | With potassium carbonate In n-heptane at 80℃; for 24h; | S4. Procedure for the synthesis of aldehydes and ketones General procedure: A magnetic stir bar, 0.5 mmol alcohol and 3 mL n-heptane solvent were added to 20 mL glass tube. Then, 35mg catalyst and 10 mol% of K2CO3 were added. The glass tube containing reaction mixture was f itted withseptum and connected to a balloon containing one bar of air. Then the glass tube was placed into a preheatedaluminum block at 85°C. Temperature inside the reaction tube was measured to be 80 oC and this temperaturehas been taken as the reaction temperature. The reaction was allowed to progress under continuous stirringfor the required time at 80 °C. Af ter completion of the reaction, the glass tube was cooled down to roomtemperature. Afterwards, the catalyst was f iltered-off and washed with ethyl acetate. The solvent f rom thef iltrate containing the reaction products was removed in vacuum and the corresponding aldehyde/ketone waspurif ied by column chromatography. All products were analyzed by GC-MS and NMR spectroscopy analysis.In the case of yields determined the by GC, 100 μL n-hexadecane was added to the reaction vial containingthe products and diluted with ethyl acetate. Then, the reaction mixture containing catalyst and products wasf iltered through a plug of silica and the filtrate containing product was analyzed by GC. |
95% | With iron (ΙΙΙ) nitrate nonahydrate; 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl; oxygen; sodium chloride In 1,2-dichloro-ethane at 25℃; for 6h; chemoselective reaction; | |
95% | With 3,3-dichloro-1,2-diphenylcyclopropene; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; Inert atmosphere; | 17 Example 17 Place a round bottom flask in a cryogenic coolant circulation tank,Add 3,3-dichloro-1,2-diphenylcyclopropene (8) (522.30 mg, 2 mmol) to the bottle under Ar protection.And 10 ml of dichloromethane,Cool the inside of the bottle to -78 ° C,Dimethyl sulfoxide (312.52 mg, 4 mmol) was added dropwise.Keep the temperature below -70 ° C, continue to stir for 30 min after the dropwise addition.Keep the temperature inside the bottle at -78 ° C - 70 ° C,Methyl 4-(hydroxymethyl)benzoate (10) (166.18 mg, 1 mmol) was added dropwise.The temperature of the dropping process does not exceed -65 ° C, and the stirring is continued for 30 min.Add triethylamine (404.76 mg, 4 mmol),Stirring was allowed to return to room temperature and the target product selectivity was 98%.After the reaction, a saturated ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with saturated NaCI.Pure 4-heptanone was obtained as a colorless liquid in a yield of 95%. |
94% | Stage #1: 4-(methoxycarbonyl)benzyl alcohol With copper(II) bromide In acetonitrile at 20℃; for 0.05h; Inert atmosphere; Stage #2: With N,N'-di-tert-butyldiaziridin-3-one In acetonitrile at 60℃; for 3h; | |
94% | With Burgess Reagent; dimethyl sulfoxide at 20℃; for 0.0833333h; Schlenk technique; Inert atmosphere; | |
93% | With ruthenium(III) trichloride hydrate; oxygen; C25H44NO2PS In 1,2-dichloro-ethane at 40℃; for 6h; | |
92% | With 2-Picolinic acid; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; manganese (II) nitrate tetrahydrate; glacial acetic acid at 25℃; for 3h; | |
92% | With ammonium hydroxide; copper (I) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In lithium hydroxide monohydrate for 24h; Reflux; Green chemistry; | |
91% | With [ReOCl3(PPh3)2]; 4,4’-dichlorodiphenyl sulfoxide In toluene for 24h; Reflux; | General procedure for the oxidation of alcohols catalyzed by ReOCl3(PPh3)2 using bis(4-chlorophenyl) sulfoxide as oxidant agent General procedure: To a solution of ReOCl3(PPh3)2 (0.083 g, 0.1 mmol) in toluene (3 mL) was added the bis(4-chlorophenyl) sulfoxide (0.271 g, 1 mmol) and the alcohol (1.0 mmol). The reaction mixture was heated at reflux temperature in air (the reaction times are indicated in Tables 1-4) and the progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was evaporated and purified by silica gel column chromatography with n-hexane to afford carbonyl compounds and bis(4-chlorophenyl) sulfide, which are all known compounds and their 1H NMR and 13C NMR data are consistent with those of the commercial products. |
91% | With double-atom catalyst FeCo-DAC In o-dimethylbenzene at 140℃; for 36h; Inert atmosphere; Sealed tube; | |
88% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In n-heptane at 80℃; for 24h; | Synthesis of Aldehydes 2a-y; General Procedure General procedure: A mixture of catalyst PS-PEG-TD2-Cu(OAc)2 (100 mg, 0.05mmol Cu), BnOH (1a, 27.0 mg, 0.25 mmol), and TEMPO (7.8 mg,0.05 mmol) in heptane (2.0 mL) was stirred at 80 °C for 24 hunder air (1 atm). The mixture was then cooled and filtered, andthe resulting solid material was washed with Et2O (3 × 2 mL).The organic phases were combined, concentrated to a volume of2 mL, and the internal standard was added to determine the GCyield. The crude product was purified by column chromatography[silica gel, hexane-Et2O (99:1)]. In the formation of somebenzaldehydes, low isolated yields were observed because ofinstability of the benzaldehydes on silica gel |
87% | With 2C36H60N9(3+)*3O4W(2-); dihydrogen peroxide In lithium hydroxide monohydrate at 20℃; for 0.05h; Green chemistry; | |
87% | With 5-nitroso-1,3-diphenyltetrazolium tetrafluoroborate; oxygen; HNO3 In acetonitrile at 20℃; for 8h; | |
86% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium carbonate; isocyanuric acid In ethyl acetate at 0 - 10℃; for 3h; | General Procedure for the oxidation of alcohols employing nitroxyl radical / imide / NaOCl in the presence of K2CO3. General procedure: To a mixture of the alcohol (3.839 mmol), K2CO3 (2.0 equiv, 7.678 mmol) and cyanuric acid (0.1 equiv, 0.384 mmol) in 20 mL of ethyl acetate were added TEMPO or AZADO (3 mol%, 0.115 mmol) and 12% NaOCl (1.2 equiv, 4.607 mmol, Wako Pure Chemical Industries, Ltd.) at 0-10°C. The mixture was then stirred to complete. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the corresponding product. |
86% | With iron(III) trichloride hexahydrate; C17H26N3(1+)*Br(1-); dihydrogen peroxide In lithium hydroxide monohydrate at 20℃; for 3h; chemoselective reaction; | |
85% | With chromium(VI) oxide; orthoperiodic acid In dichloromethane; acetonitrile at -40℃; for 1h; | |
85% | With iron (ΙΙΙ) nitrate nonahydrate; TEMPOL; oxygen; oxalic acid In lithium hydroxide monohydrate at 50℃; for 3h; | 6 Example 6: Synthesis of methyl p-formylbenzoate Under oxygen atmosphere, add Fe(NO3)3·9H2O (97.0 mg, 0.24 mmol), H2C2O4·2H2O (30.3 mg, 0.24 mmol), 4-OH-TEMPO (46.5 mg, 0.27 mmol), After regular stirring, add 2 mL H2O, methyl p-hydroxymethyl benzoate (498.5 mg, 3 mmol), and react at 50 for 3 h. After the reaction,Add a small amount of ethyl acetate to the mixture, then add sodium chloride to salt out,After filtration, it was extracted with 12 mL of ethyl acetate, dried with anhydrous sodium sulfate,Purification by column chromatography (using a mixed solvent with a volume ratio of ethyl acetate/petroleum ether of 1:10 as the eluent), the yield was 85%. |
84% | With 1-methyl-1H-imidazole; [2,2]bipyridinyl; copper (I) iodide; 1,3-diphenyltetrazolium-5-hydroxyamide; oxygen In acetonitrile at 20℃; for 3h; chemoselective reaction; | General Procedure for the Optimization of the Cu-1-CatalyzedAerobic Oxidation of Benzyl Alcohol (Table 1): General procedure: Amixture of benzyl alcohol 2a (0.4 mmol), Cu salt (0.02 mmol)ligand (0.02 mmol), base (0.04 mmol), and 1 (0.02 mmol) wasvigorously stirred in MeCN (4.0 mL) at room temperature for 24h in the presence of PhCN (0.2 mmol) as an internal standard. Atintervals, aliquots were analyzed by GC after being passedthrough a SiO2 column eluted with CH2Cl2. The yield of benzaldehyde3a (tR = 4.3 min) and the recovery of 2a (tR = 9.4 min)were calculated on the basis of calibration curves by usingauthentic samples |
83% | With iodine; oxygen In ethyl acetate at 20℃; for 24h; visible light irradiation; | |
83% | With chloramine-T; anhydrous zinc bromide In acetonitrile for 3h; Reflux; | Experimental Procedures for oxidation of Various alcohols: General procedure: A CH3CN solution of alcohol (1 mmol), ZnBr2 (45 mg, 0.2 mmol), and chloramine-T (282 mg, 1 mmol) was placed in a three necked flask with a reflux condenser. After the mixture was stirred under reflux for 1.5-5 h. After cooling to room temperature, the solution was quenched by adding water and the resulting mixture was extracted with AcOEt. Removal of the solvent under reduced pressure gave the crude product, which was purified by column chromatography on silica gel to give the corresponding carbonyls. |
83% | With dihydrogen peroxide In lithium hydroxide monohydrate at 80℃; | 2.4 Reaction Conditions General procedure: In a typical process, benzyl alcohol (1 mmol), Cat.(0.5 mmol), 30 % aq H2O2 (2 mmol) were mixed and H2O(5 mL) was then added. The reaction mixture was refluxedat 80-85 °C for 28 h. The progress of the reaction wasmonitored by the TLC with samples taken periodically.After the completion of the reaction, the system cooledto room temperature. The catalyst was filtered and the filtrateextracted three times with Et2O. The organic layerwas dried over anhydrous MgSO4 and evaporated underreduced pressure. The product was purified by columnchromatograph to give benzaldehyde (98 % yield). The nextrun was performed under identical reaction conditions. Theproducts were recognized by comparing experimental datawith authentic samples. |
82% | With HNO3; ytterbium(III) tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane for 2h; Heating; | |
82% | Stage #1: 4-(methoxycarbonyl)benzyl alcohol With C6H13N2O(1+)*C6H12N2O*C24H20B(1-) In acetonitrile at 20℃; for 0.166667h; Stage #2: With tetrapropylammonium perruthenate (VII) In acetonitrile at 20℃; for 16h; | |
76.5% | Stage #1: 4-(methoxycarbonyl)benzyl alcohol With bis(trichloromethyl) carbonate; 4-(2-(2-(methylsulfinyl)ethyl)-4-nitrophenyl)morpholine In dichloromethane at -15℃; for 1h; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at -15℃; Inert atmosphere; | Typical procedure for the oxidation of alcohols General procedure: A solution of BTC (0.41 g, 1.39 mmol) in dry CH2Cl2 (5 mL) was cooled in an ice-salt bath under an atmosphere of N2. A solution of I (1.24 g, 4.17 mmol) in dry CH2Cl2 (5 mL) was added dropwise for 0.5 h, at -15 °C. Stirring was continued for 0.5 h, and a solution of benzyl alcohol (0.3 g, 2.78 mmol) in dry CH2Cl2 (5 mL) was added dropwise for 0.5 h, at-15 °C. After stirring for 0.5 h, Et3N (0.84 g, 8.34 mmol) was added slowly while the temperature should be controlled below -15 °C. When the reaction was completed, 10% HCl solution in water was added dropwise until the pH of the reaction solution reached 2 under ice bath. The mixture was extracted with n-hexane or petroleum ether (10 mL x 2),decanted. The product was acquired after organic layer was concentrated and purified by flash chromatography (SiO2; n-hexane). (0.27 g, 92%). The water layer was used for the recovery of V and the excess I. |
76% | With Quinuclidine; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile In dimethyl sulfoxide; acetonitrile at 20℃; for 20h; Molecular sieve; Irradiation; Sealed tube; Green chemistry; | 3. General procedure for oxidation of benzylic primary and secondary alcohols General procedure: In a dry tube containing 4CzlPN (4.7 mg, 3mol%), quinuclidine (2.2mg, 10mol%), Bu4NH2PO4 (17mg, 25 mol%), MS (200 mg) in MeCN (1 ml) and DMSO (0.1 mL), benzyl primary and secondary alcohols (0.20 mmol) was added. The tube was sealed with an air balloon, and was left stirring under blue LEDs irradiation for 10 h. The desired product was isolated after purification by column chromatography. |
71% | With Bromotrichloromethane; [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[2-(2-pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate In acetonitrile at 20℃; for 24h; Schlenk technique; Irradiation; Inert atmosphere; | General Procedure for synthesis of product General procedure: An 25 mL oven-dried Schlenk tube was equipped with a stirring bar, alcohols 1 (0.5 mmol) and Ir(ppy)2(dtbbpy)PF6 (0.005 mmol, 1 mol%). The mixture was degassed by using standard Schlenk techniques with an oil pump. Then MeCN (4 mL) and bromotrichloromethane (0.75 mmol, 1.5 eq) were injected into the reaction tube. The reaction mixture was placed under a 7 W blue LED and stirred at room temperature. After 24 h, the mixture was concentrated under reduced pressure using a rotary evaporator and the purification was done by column chromatography on silica gel (200-300 mesh) with petroleum ether / ethyl acetate as the eluent to give the pure product |
69% | With tetrapropylammonium perruthenate (VII); N,N,N′,N′-tetramethylethylenediamine dioxide In dichloromethane at 20℃; for 4h; Molecular sieve; Inert atmosphere; | |
64% | With acetic anhydride; glacial acetic acid In dimethyl sulfoxide at 60℃; for 0.166667h; Microwave irradiation; Green chemistry; | 10 Example 10 Add 10a (0.60mmol, 0.1g), DMSO 1.85mL, Ac2O 1.30mL, AcOH 0.23mL into a 15mL microwave reaction tube in turn, microwave power 150w, heating temperature 60°C, reaction time 10min,After cooling, NaHCO3 solution was added and stirred at room temperature for 30 min. Extract with ethyl acetate, collect the organic phase, and extract the aqueous phase with ethyl acetate 2-3 times.The organic phases were combined, washed with water in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 10b (yield: 64%). |
63.1% | With oxygen; La0.25CoO(x) In acetonitrile at 120℃; Autoclave; | 2.3. Catalytic performance General procedure: Benzyl alcohol (28.8 mmol, 3.0 mL) and catalyst (0.100 g) were added into an autoclave. The autoclave was sealed and purged three times with 0.1 MPa O2. At the room temperature, the autoclave was filled with 1.0 MPa O2. Then, the reaction was conducted at 120 °C for 10 h. Concentrations of benzaldehyde and benzyl alcohol were determined by a HPLC (YILITE LC 3000-2 series instrument) using an Ultimate MBC18 (250 mm x 4.60 mm) column by UV detector at 254 nm wavelength (Fig. S1). The mobile phase consisted of a methanol/water solution 25/75 (V/V) fed at a flow-rate of 1.0 mL/min. The yield and selectivity of the benzaldehyde were calculated according to the formula: |
59% | With palladium diacetate; oxygen In dimethyl sulfoxide at 80℃; for 72h; | |
59% | With indium trifluoromethanesulfonate; chloramine-T In acetonitrile for 3h; Reflux; Inert atmosphere; | General Experimental Procedure General procedure: The starting 1-(paratolyl)ethanol (1 mmol), chloramine-T (1 mmol), and In(OTf)3(0.3 mmol) were dissolved in CH3CN (10 mL) in a 100 mLflask equipped with a magnetic stirrer and a reflux condenser.The reaction mixture was heated at reflux for 3 h under anArgon atmosphere and was monitored for completion by TLC.After the reaction mixture was cooled to room temperature,the solvent was removed via rotary evaporation. The residueof the reaction mixture was separated through flash columnchromatography on silica gel. The obtained product was confirmed by spectroscopy. |
57% | With cerium(III) trichloride heptahydrate; Sodium hydrogenocarbonate In acetonitrile at 50℃; for 35h; Irradiation; Sealed tube; | General procedure (GP1) General procedure: A 10 mL glass vial equipped with a teflon-coated stirring bar was charged with benzylic alcohol 1 (0.2 mmol), CeCl3·7H2O (10 mol %), and NaHCO3 (10 mol%). The glass vial was sealed with a PTFE septum. Then, solvent (2 mL) was added and the reaction was opened to air via a needle. The reaction was placed in a pre-programed temperature (50 °C) controlled blue LED reactor (as shown in Figure S1) and the reaction mixture was irradiated with a 455 nm blue LED. After 35-48 hours, the reaction mixture was concentrated under reduced pressure. Product 2 was purified by flash chromatography on silica using hexane and AcOEt. |
57% | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; tetra-n-butylammonium azide In acetonitrile at 25℃; for 24h; Irradiation; | |
40% | With indium(III) isopropoxide; 2,2-dimethypropanal In chloroform at 20℃; for 3h; Glovebox; Sealed tube; Inert atmosphere; | Oppenauer Oxidation of Alcohols Using In(i-OPr)3; General Procedure General procedure: To a screw tube in a glovebox was added In(Oi-Pr)3 (29.2 mg, 0.1 mmol). The tube was then sealed and removed from the glovebox, and CHCl3 (1 mL), alcohol (0.5 mmol), and pivalaldehyde (280 μL, 2.5 mmol) were added under N2 in this order. After stirring the mixture at r.t. for 3 h, H2O (1.0 mL) was added to the reaction mixture, which was then extracted with EtOAc. The organic phase was dried (Na2SO4), and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (Table 2 and Scheme 2). |
37% | With [Rh((5-H-dibenzo[a,d]cyclohepten-5-yl)2NH)(PPh3)]OTf; potassium carbonate; Nitrosobenzene In tetrahydrofuran at 20℃; | |
18% | With Dess-Martin periodane In dichloromethane at 20℃; for 12h; | |
With pyridinium fluorochromate In dimethyl sulfoxide at 24.9℃; ΔH(excit.), ΔS(excit.); | ||
With perchloric acid; N-Chlorourethan In glacial acetic acid at 24.9℃; for 12h; ΔH(excit.), ΔS(excit.), ΔG(excit.), further temperature, in the dark; | ||
With pyridinium bromochromate In dimethyl sulfoxide at 24.9℃; for 15h; var. temp.; ΔH(excit.), ΔS(excit.), ΔG(excit.); | ||
With bis(2,2'-bipyridyl) copper(II) permanganate In glacial acetic acid at 9.9 - 29.9℃; | ||
With N,N,N-trimethylbenzenemethanaminium dichloroiodate; glacial acetic acid; anhydrous zinc chloride at 24.85℃; for 15h; ΔH(excit.), ΔS(excit.); | ||
With benzyltrimethylammonium tribromide; glacial acetic acid In lithium hydroxide monohydrate | ||
With oxoammonium resin In dichloromethane at 20℃; for 1h; | ||
With Mn(N,N'-ethylenebis(salicylaldiminato))O In acetonitrile at 24.85℃; for 12h; | ||
With benzyltrimethylammonium chlorobromate; glacial acetic acid at 34.85℃; | ||
With quinolinium fluorochromate In dimethyl sulfoxide at 14.85℃; | ||
With tetra-N-butylammonium tribromide; potassium bromide In lithium hydroxide monohydrate; glacial acetic acid at 14.85℃; for 12h; | ||
With quinolinium bromochromate In dimethyl sulfoxide at 34.85℃; | ||
With perchloric acid; bis-[(trifluoroacetoxy)iodo]benzene In lithium hydroxide monohydrate; glacial acetic acid at 14.85℃; | ||
With manganese(IV) oxide In tetrahydrofuran at 20℃; | ||
With manganese(IV) oxide In tetrahydrofuran at 20℃; for 4h; | ||
With manganese(IV) oxide In dichloromethane at 20℃; for 24h; | ||
With morpholinium chlorochromate In dimethyl sulfoxide at 24.84℃; | ||
With 2,2'-bipyridiniumchlorochromate In dimethyl sulfoxide at 24.84℃; | ||
With 2',3',4',5'-tetra-O-acetylriboflavin; air In dimethylsulfoxide-d6; water-d2 at 20℃; for 0.416667h; Irradiation; | ||
With oxygen In trifluorotoluene at 100℃; for 3h; UV-irradiation; Autoclave; | ||
60 %Chromat. | With C16H13ClIrNO(1-); Sodium hydrogenocarbonate In para-xylene for 20h; Reflux; Inert atmosphere; | |
77 %Chromat. | With [Cp*Ir(6,6'-dihydroxy-2,2'-bipyridine)(H2O)](OTf)2 In lithium hydroxide monohydrate for 20h; Inert atmosphere; Reflux; | |
80 %Spectr. | With Cp*Ir(6,6'-dionato-2,2'-bipyridine)(H2O) In <i>tert</i>-butyl alcohol at 130℃; for 20h; | |
69 %Chromat. | With Isopropenyl acetate; C16H21ClIrNO In toluene at 80℃; for 10h; Inert atmosphere; | General Procedure for the Hydrogen Transfer Oxidation of Benzylic Primary Alcohols Shown in Table 4 General procedure: Under an atmosphere of argon, catalyst 2e (2.0 mol%), benzylic primary alcohol (1.0 mmol), isopropenyl acetate (1.0 mmol), and toluene (18 mL) were placed in a flask. The mixture was stirred at 80 °C for 10 h. The conversion of benzylic primary alcohol and the yield of benzaldehyde derivative were determined by GC analysis using biphenyl as an internal standard. |
75 %Spectr. | Stage #1: 4-(methoxycarbonyl)benzyl alcohol With C24H20B(1-)*C5H12NO2(1+)*C5H11NO2 In acetonitrile at 20℃; for 0.166667h; Stage #2: With tetrapropylammonium perruthenate (VII) In acetonitrile at 20℃; | |
With oxygen In diethyl ether; lithium hydroxide monohydrate at 30℃; for 15h; chemoselective reaction; | General procedure of the catalytic reaction General procedure: 1 mmol benzyl alcohol, 1.375 g catalyst, 20 ml water, and15 ml ether were mixed in a flask (50 ml). A balloon wasused to introduce O2 at ambient pressure, keeping the temperatureat 30 °C for a given time. At the end of the reaction,a few drops of diluted HCl solution (1 mol/L) wereadded to the reaction system, and the pH of water wasadjusted to 3-4. After stirring, the catalyst was transferredinto the water and the upper organic layer was isolated forGC analysis. | |
With potassium fluoride; 2-fluoropyridine; trifluoromethane sulfonic acid silver salt; trimethyl(trifluoromethyl)silane; 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In ethyl acetate at 20℃; for 12h; Glovebox; Inert atmosphere; | ||
83 %Chromat. | With 7,8-dimethyl-10-(tetra-<i>O</i>-acetyl-<i>D</i>-xylitol-1-yl)-10<i>H</i>-benzo[<i>g</i>]pteridine-2,4-dione; [(TPA)FeII(CH3CN)2](ClO4)2 In lithium hydroxide monohydrate; acetonitrile at 20℃; for 4.5h; UV-irradiation; | |
With dihydrogen peroxide In lithium hydroxide monohydrate at 110℃; for 48h; Schlenk technique; Green chemistry; | ||
99 %Chromat. | With [2,2]bipyridinyl; iron (ΙΙΙ) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; glacial acetic acid at 80℃; for 0.5h; | |
With lithium hydroxide monohydrate; oxygen In dichloromethane at 25℃; for 24h; | ||
57 %Chromat. | With [(pentamethylcyclopentadienyl)Ir(4-methyl-5-trifluoromethyl-2-pyridonate)Cl] In toluene at 135℃; for 20h; Inert atmosphere; Schlenk technique; | 2.7 Procedures for acceptorless dehydrogenation of primary alcohols catalyzed by 2bc (Table5) General procedure: A solution of an alcohol (0.5mmol) and catalyst 2bc (5.7mg, 0.01mmol) in toluene (9mL) was refluxed for 20hat 135°C (oil bath temperature). In the reaction of cyclohexylmethanol, p-xylene was used as the solvent and the solution was refluxed for 20hat 160°C (oil bath temperature). After the mixture was cooled to room temperature, biphenyl (25mg) was added as an internal standard. The mixture was analyzed by GC using an authentic sample. The results are shown in Table5 . |
62 %Spectr. | With bismuth vanadate; oxygen In acetonitrile at 40℃; for 8h; Schlenk technique; Irradiation; | 2.4. Photocatalytic reactions General procedure: Bismuth vanadate (32.3 mg, 100 mmol) was added to a Schlenkflask containing benzyl alcohol stock solution (1 mL, 0.1 mmol inacetonitrile) and acetonitrile (9 mL). The mixture was left to stirfor 30 min to disperse the catalyst under a dioxygen atmospherevia a balloon. The mixture was then irradiated with a 30W blueLED array at a distance of 2 cmwith an irradiance of 245mWcm2.The mixture reached ca. 40 °C by the end of the reaction and afterirradiation, the catalyst was removed using centrifugation at4000 rpm for 30 min. For GC analysis, 1 mL of supernatant wastaken and 1 lL injected. For NMR analysis, the supernatant wasreduced in volume using a rotary evaporator at 65 mbar at 20 °C,and the residue dissolved in d6-DMSO containing maleic acid asan internal standard. |
81 %Chromat. | With oxygen In toluene at 100℃; for 36h; chemoselective reaction; | |
With sulfur(VI) fluoride; potassium carbonate; dimethyl sulfoxide at 20℃; for 12h; | ||
35 %Chromat. | With para-bromotoluene; potassium carbonate In acetonitrile at 30℃; for 10h; Inert atmosphere; Irradiation; | |
With toluene-4-sulfonic acid; benzimidazolium dichromate In dimethyl sulfoxide at 24.84℃; for 12h; Darkness; | Product analysis: General procedure: The product analysis was carried out under kinetic conditions. In a typical experiment, benzyl alcohol(0.1 mol), TsOH (1.0 mol) and BIDC (0.02 mol) were made up to 50 ml in DMSO and kept in the dark for ca. 12 h to ensure completion of the reaction. The solution was then treated with excess (200 ml) of a saturated solution of 2,4-dinitrophenylhydrazine in 2 mol dm3 HCl and kept overnight in a refrigerator. The precipitated 2,4-dinitrophenylhydrazone(DNP) was filtered off, dried, weighed, recrystallized from ethanol, and weighed again. The yields of DNP before and after recrystallization were 7.89 g (92%) and 6.86 g (80%)respectively, indicating the amount of benzaldehyde formed is about 3.0-3.1 g. The DNP was found identical (m.p. andmixed m.p.) with the DNP of benzaldehyde. The identity of the DNP was confirmed by the elemental analysis also. The observed values were C, 54.79%; H, 3.40% and N, 19.39%,the calculated values for C13H10N4O4 are C, 54.55%; H,3.50% and N, 19.58%. In similar experiments, with the other substituted benzyl alcohols the yields of DNP, after recrystallization, were in the range of 75 88%. CrVI is reduced to CrIII. | |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 0.5h; Inert atmosphere; | Transformation of Primary Alcohols 1 into Diethyl 3-Aryl- or 3-Alkylisoxazole-4,5-dicarboxylates 4; Typical Procedure General procedure: DIB (354.0 mg, 1.1 mmol) was added to a solution of p-methylbenzyl alcohol 1A (122.2 mg, 1.0 mmol) and TEMPO (15.6 mg, 0.1 mmol) in CH2Cl2 (2.0 mL). The mixture was stirred at r.t. under Ar atmosphere. After 30 min, NH2OH·HCl (104.2 mg, 1.5 mmol) and K2CO3 (103.7 mg, 0.75 mmol) were added and the obtained mixture was stirred for 18 h at r.t. Then, DMF (0.2 mL) and NCS (200.1 mg, 1.5 mmol) were added to the solution at 0 °C. After 1 h, the reaction mixture was stirred for 3 h at r.t., then Et3N (209.1 L, 1.5 mmol) and diethyl acetylenedicarboxylate (238.5 L, 1.5 mmol) were added to the solution and the obtained mixture was stirred for 1 h at r.t. The mixture was quenched with sat. aq. NaHCO3 and extracted with CHCl3 (3 × 10.0 mL), and the organic layer was dried over Na2SO4. After removal of the solvent, purification by short column chromatography on silica gel (hexane/ EtOAc, 8:1) gave diethyl 3-(p-methylphenyl)isoxazole-4,5-dicarboxylate 4A (266.9 mg, 88%). | |
> 99 %Chromat. | With 1-methyl-1H-imidazole; copper (I) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; C12H8F3NOS In acetonitrile at 20℃; for 3h; | 2.3. Oxidations General procedure: Oxidation reactions were performed in 3 ml or 5 ml MeCN solutionsat room temperature under open air conditions. The reaction was set upby adding 4 mol% of copper(I)iodine, 4 mol% of ligand, solvent, 5 mol%of TEMPO, 1 mmol of alcohol and 10 mol% of NMI into a 20 ml test tube,which was equipped with a magnetic stir bar. The reaction was stirred at 1500 rpm for 1 h, 3 h or 24 h depending on the substrate.After the reaction, the reaction solution and an internal standard(acetophenone 40 μL or 1,2-dichlorobenzene 40 μL, see ESI for moreinformation) were diluted with EtOAc (50 mL). GC samples (1.5 mL)were prepared by filtrating the solution through a layer of silica gel (1cm thick). The yields were determined using GC-FID with calibration curves and identified using GC-MS and/or 1H/13C/HMBC/HSQC NMR. |
>99 %Chromat. | With copper (I) iodide; di(pyridin-2-yl)amine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; for 4h; | Oxidations General procedure: Oxidation reactions were performed in 3 mL MeCN or in a mixture of2 mL MeCN and 1 mL H2O solutions at room temperature under open airconditions. The reaction was set up by adding 2.5 mol% of copper(I)iodine, 2.5 mol% of ligand, 3 mL solvent, 4 mol% of TEMPO and 1 mmol of alcohol into a 20 ml test tube, which was equipped with a magneticstir bar. The reaction was stirred at 1500 rpm for 1 h, 3 h or 24 h depending on the substrate. After the reaction, the reaction solution andan internal standard (acetophenone 40 μL or 1,2-dichlorobenzene 40 μL,see ESI for more information) were diluted with EtOAc (50 mL). GCsamples (1.5 mL) were prepared by filtrating the solution through alayer of silica gel (1 cm thick). The yields were determined using GC-FIDwith calibration curves and identified using GC-MS and/or 1H/13C/HMBC/HSQC NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tetrahydridoborate In ethanol at 5℃; for 0.5h; | |
100% | With zirconium(IV) hydrous oxide hydroxide; isopropanol at 60℃; for 0.133333h; | |
99% | Stage #1: methyl 4-formylbenzoate With PMHS; ferrous acetate; tricyclohexylphosphine In tetrahydrofuran at 65℃; for 16h; Stage #2: With Sodium hydrogenocarbonate In tetrahydrofuran; methanol at 0 - 20℃; Further stages.; |
99% | With iron(II) fluoro{tris[2-(diphenylphosphino)phenyl]phospino}tetrafluoroborate; hydrogen; trifluoroacetic acid In isopropanol at 120℃; for 5h; Inert atmosphere; Autoclave; chemoselective reaction; | |
99% | With sodium tetrahydridoborate; ethanol at 0 - 5℃; for 1.5h; | 4a Example 4a Preparation of methyl 4-(hydroxymethyl)benzoate Into a three neck, 1 L round bottom flask fitted with a thermocouple probe was added methyl 4-formylbenzoate (16.6 g, 100 mmol) and EtOH (250 mL). The solution was cooled in an ice bath and NaBH4 (1.17 g, 31.0 mmol) was added portionwise over 30 min keeping the internal temperature below 5 °C. After stirring for 1 hr, the reaction was quenched by the addition of a small amount of acetone, followed by AcOH (10 mL). The reaction mixture was then allowed to warm to rt, and was stirred for 16 hrs. The quenched reaction mixture was diluted with H20 and made basic by the careful addition of solid Na2C03. The mixture was concentrated in vacuo to remove most of the EtOH. The resulting residue was diluted with EtOAc and additional H20. The layers were separated and the basic aqueous layer was further extracted with EtOAc (3 x). The organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound as a white solid (16.5 g, 99.4 mmol, 99 % yield). MS (ESI) 166 [M+H]+. 1H NMR (400 MHz, CDC13) δ ppm 8.00 (d, J= 8.3 Hz, 2H), 7.41 (d, J= 8.5 Hz, 2H), 4.74 (s, 2H), 3.90 (s, 3H), 2.34 (s, 1H). |
99% | With hydrogen In ethanol; water monomer at 40℃; for 0.00611111h; Flow reactor; Green chemistry; chemoselective reaction; | |
99% | With hydrogen; anhydrous silver perchlorate; 1,1,1,3,3,3-hexamethyldisilazane potassium In toluene at 25℃; for 17h; Glovebox; chemoselective reaction; | |
98% | With Na(1+)*C12H33AlNO4Si2(1-) In tetrahydrofuran; toluene at 0℃; for 1h; Inert atmosphere; chemoselective reaction; | Representative procedure for the chemoselective reduction of multifunctionalized compounds with new modified Red-Al General procedure: A dry and argon-flushed flask, equipped with a magnetic stirring bar and septum, was charged with 4-acetylbenzaldehyde (1.0 mmol) and THF (10 mL). After cooling to 0 C, the modified Red-Al (0.5 M, 2.2 mL in THF) was added dropwise and the mixture was stirred for 1 h at 0 C. The reaction was quenched with 1 N aqueous HCl (10 mL) and the product was extracted with diethylether (10 mL). The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and the crude residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1:5 v/v) to affording the desired alcohol (123 mg, 83% yield). |
98% | With formic acid; C20H29ClIrN4(1+)*Cl(1-) In water monomer at 80℃; for 0.0833333h; chemoselective reaction; | |
98% | With C22H26ClIrN4; hydrogen In ethanol; water monomer at 30℃; for 2h; chemoselective reaction; | |
98% | With phenylsilane; [NiCp{Bn-NHC-(CH2)2StBu}](PF6) In tetrahydrofuran at 40℃; for 4h; Inert atmosphere; Schlenk technique; | |
97% | With decaborane In tetrahydrofuran; water monomer at 20℃; for 0.5h; | |
97% | With formic acid; iron(II) tetrafluoroborate hexahydrate; tris(2-diphenylphosphinoethyl)phosphine In tetrahydrofuran at 60℃; for 2h; Schlenk technique; Inert atmosphere; | 2. Experimental General procedure: Fe(BF4)2·6H2O (0.7 mg; 0.002 mmol) and tris[2-(diphenyl-phosphino)-ethyl]phosphine [P(CH2CH2PPh2)3; tetraphos] (1.4 mg; 0.002 mmol) are placed in a Schlenk-tube under argon atmosphere. 1 mL dry tetrahydrofurane is added and the purple solution is stirred for 2 min. Cinnamaldehyde (63 μL; 0.5 mmol) and 100 μL n-hexadecane as an internal GC-standard are injected and a sample is taken for GC-analysis. The solution is heated to 60 °C and the reaction starts by addition of 1.1 equiv formic acid (22 μL; 0.55 mmol). After 2 h, a second sample is taken for GC-analysis and conversion and yield are determined by comparison with authentic samples. For the isolation, the reaction is scaled up by a factor of 20. When the reaction is completed, the reaction solution is diluted with a mixture of n-hexane and ethyl acetate (3:1), filtered through a plug of silica and the solvent removed in vacuum. |
97% | With Co-doped ammonia borane In methanol at 20℃; for 0.0833333h; chemoselective reaction; | |
97% | Stage #1: methyl 4-formylbenzoate With [Ru(2-(ethylthio)-N-[(pyridin-2-yl)methyl]ethan-1-amine)(triphenylphosphine)Cl2]; potassium-t-butoxide In isopropanol Autoclave; Inert atmosphere; Stage #2: With hydrogen In isopropanol at 80℃; for 1h; | |
96% | With trimethylamine-N-oxide; anhydrous sodium formate; C34H44FeN4O4(2+)*2I(1-) In water monomer at 80℃; for 24h; Inert atmosphere; Schlenk technique; | General procedure A for reduction of aldehydes by hydrogen transfer reaction General procedure: In a dried flamed Schlenk tube under argon, the corresponding aldehyde (1 equiv.) and sodiumformate (170 mg, 5 equiv.) were mixed in water (0.5 M). The iron complex Fe4 (5 mg, 2 mol%) and Me3NO (1 mg, 2.5 mol %) were then added. The mixture was stirred and heated at 80°C for 24 h. After cooling-down to room temperature, the resulting solution was quenchedwith a saturated aqueous solution of sodium bicarbonate and extracted three times with ethylacetate. The organic phase was dried over MgSO4, filtrated and concentrated under vacuumto afford the crude product. A purification by flash chromatography on silica gel furnished thealcohol. |
95% | With ammonia hydrochloride; zinc powder In tetrahydrofuran; water monomer at 20℃; for 0.333333h; | |
95% | With Cp*Ir(6,6'-dionato-2,2'-bipyridine)(H2O); hydrogen In tert-Amyl alcohol at 30℃; for 12h; Green chemistry; chemoselective reaction; | 4.4. General procedure for catalytic hydrogenation of 4 General procedure: To an oven-dried 5 mL round-bottom flask were added aldehyde (1 mmol), cat. 7 (2.7 mg, 0.5 mol %) and tert-amyl alcohol (1 mL). Next, vacuum was applied to the flask followed by filling with H2 gas and keeping the flask attached to a balloon filled with H2 gas. The mixture was heated at 30 °C for 12 h. After completion of the reaction, the solvent was removed by evaporation under reduced pressure. The alcohols were isolated and purified by filtering a hexanes/ethyl acetate (5:1) solution of the crude product through a pad of silica gel, and then removing the solvent under reduced pressure. The conversion and purity of the alcohol products was assessed using NMR spectroscopy. |
95% | With C46H49CoN3P4(2+)*2BF4(1-); hydrogen; potassium hydroxide In ethanol; acetonitrile at 60℃; for 24h; Autoclave; Glovebox; chemoselective reaction; | |
95% | With [Cp*Ir(2,2'-bpyO)(OH)][Na]; hydrogen In water monomer at 30℃; for 12h; Green chemistry; | 4.1. General procedure for catalytic hydrogenation of ketones,aldehydes or unsaturated aldehydes General procedure: To an oven-dried 5 mL round-bottom flask were added ketonesor aldehydes or unsaturated aldehydes (1 mmol), cat. 6 (5.5 mg,1 mol %) and H2O (1 mL). Next, vacuum was applied to the flask followedby filling with H2 gas and keeping the flask attached to a balloonfilled with H2 gas. The mixture was heated at 30 °C for 12 h.After completion of the reaction, the mixture was extracted withethyl acetate (5 mL x 3). Then, the ethyl acetate layers were combined, dried with anhydrous sodium sulfate, filtered, and concentratedby evaporation under reduced pressure. The alcohols wereisolated and purified by filtering a hexanes/ethyl acetate (8:1)solution of the crude product through a pad of silica gel. Thenthe solvent was removed under reduced pressure to afford the correspondingproducts. The purity of alcohol products was assessedusing 1H NMR spectroscopy. |
95% | With KB3H8 In tetrahydrofuran at 20℃; for 9h; Green chemistry; | |
94% | With sodium borohydride In methanol | p-Methoxycarbonylbenzyl Alcohol p-Methoxycarbonylbenzyl Alcohol A stirred solution of p-methoxycarbonylbenzaldehyde (Description 35, 0.82 g, 5.0 mmol) in methanol (10 ml) at 0° under argon was treated with sodium borohydride (50 mg, 1.25 mmol), added in portions over 5 minutes. After stirring overnight the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and dried (MgSO4). Removal of the solvent gave the desired product as a colourless solid (0.78 g, 94%). δH (CDCl3) 1.83 (1H, t, J 5.9 Hz), 3.93 (3H, s), 4.78 (1H, d, J 5.9 Hz), 7.45 (2H, d, J 8.1 Hz), 8.04 (2H, d, J 8.1 Hz) ppm. |
94% | With indium(III) isopropoxide; isopropanol for 0.5h; Inert atmosphere; | |
94% | With borane-ammonia In tetrahydrofuran at 20℃; for 0.25h; | |
93% | With hydrogen In water monomer at 20℃; for 11h; Green chemistry; chemoselective reaction; | |
93% | With Cp*Ir(6,6'-dionato-2,2'-bipyridine)(H2O); isopropanol at 82℃; for 6h; Inert atmosphere; Schlenk technique; chemoselective reaction; | |
92% | With isopropanol at 337℃; for 0.366667h; | |
92% | With potassium diisobutyl-t-butoxy aluminum hydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; chemoselective reaction; | 4.5 Chemoselective reduction of dicarbonyl compounds with PDBBA (Table3) General procedure: A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with dicarbonyl compound (1.0 mmol) and 10 mL THF. After cooling to 0°C, PDBBA (1.3 mmol) was added dropwise and stirred for 1h at same temperature. The reaction was stopped by the aqueous 1N HCl (10mL) and extracted with diethyl ether (2×10mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel afforded the desired product. |
92% | With [Cp*Ir(2,2'-bpyO)(OH)][Na]; hydrogen In water monomer at 30℃; for 12h; | 14 The method is: methyl 4-formylbenzoate (164 mg, 1.0 mmol), metal iridium complex [Cp*Ir(2,2'-bpyO)(OH)][Na](4.6 mg, 0.01 mmol) , 1 mol%) and water (1 mL) were sequentially added to a 25 mL round-bottom flask, the air in the round-bottom flask was replaced with hydrogen, and the hydrogen pressure in the system was maintained at 1 standard during the entire reaction. At atmospheric pressure, the reaction mixture was reacted at 30°C in a hydrogen atmosphere for 12 hours. After the reaction, the solvent was removed by rotary evaporation, and then column chromatography (developing solvent: petroleum ether/ethyl acetate volume ratio=8:1) was used to obtain the pure target compound, yield: 92%. |
90% | In toluene | 1 STEP (1) STEP (1) A mixture of methyl 4-formylbenzoate (500 g, 3.05 mole), Raney nickel (25 g) and toluene (1000 mL) is heated in an autoclave between 60 and 75° C. under a hydrogen atmosphere at between 41 and 44 bars absolute for 3.5 hours. The hydrogen pressure then is released and the catalyst removed from the reaction mixture by filtration at 40° to 60° C. The toluene is removed by distillation and the product, methyl 4-(hydroxymethyl)benzoate obtained in a 90% yield, is used in the next step without further purification. |
90% | Stage #1: methyl 4-formylbenzoate With C27H43AlClN3Si3; 4,4,5,5-tetramethyl-1,3,2-dioxaborolane In neat (no solvent) at 20℃; for 3h; Stage #2: With mesoporous silica at 20℃; | |
89% | Stage #1: methyl 4-formylbenzoate With tetrabutylammonium tricarbonylnitrosylferrate; tricyclohexylphosphine In 1,4-dioxane at 50℃; Inert atmosphere; Stage #2: With water monomer; sodium hydroxide In 1,4-dioxane; methanol at 20℃; for 1.5h; Inert atmosphere; chemoselective reaction; | |
89% | Stage #1: methyl 4-formylbenzoate With Triethoxysilane; [cis-Fe(H)(SPh)(PMe3)4] In tetrahydrofuran at 50℃; for 2h; Stage #2: With methanol; sodium hydroxide In tetrahydrofuran; water monomer at 60℃; for 24h; | 2.2. General procedure for catalytic hydrosilylation of aldehydes General procedure: To a 25 mL Schlenk tube containing a solution of 1 in 2 mL of THF was added an aldehyde (1.0 mmol) and (EtO)3 SiH (0.20 g, 1.2 mmol). The reaction mixture was stirred at 50-55 °C until there was no aldehyde left (monitored by TLC and GC-MS). The reaction was then quenched byMeOH (2mL) and a 10% aqueous solution of NaOH (5 mL) with vigorous stirring at 60 °C for about 24 h.The organic product was extracted with diethyl ether (10 mL × 3), dried over anhydrous MgSO4, and concentrated under vacuum. The alcohol product was further purified using flash column chromatography (elute with 5-10% ethyl acetate in petroleum ether). The 1H NMR and 13C NMR spectra of the alcohol products are providedin Supporting information. |
89% | With CdS(x)Se(1-x) x:0-1;; caesium acetate; para-thiocresol In toluene for 15h; Sealed tube; Inert atmosphere; Irradiation; | |
88% | With sodium tetrahydridoborate; 1,4,8,11,15,18,22,25-octapentyloxyphthalocyaninato nickel In pentan-1-ol at 25℃; for 0.666667h; | |
87% | With ReOBr2(hmpbta)(PPh3); phenylsilane In tetrahydrofuran for 0.333333h; Reflux; chemoselective reaction; | General procedure: In a typical experiment, to a mixture of carbonyl compound (1.0mmol) and [ReOBr2(hmpbta)(PPh3)] (5mol%) in THF (3mL) at reflux temperature was added PhSiH3 (2.0mmol). The reaction mixture was stirred under air atmosphere (the reaction times are indicated in the Table 4) and the progress of the reaction was monitored by TLC or 1H NMR. Upon completion, the reaction was quenched with 1equiv of tetrabutylammonium fluoride (TBAF) (1.0M THF) during 1h. Then, the reaction mixture was evaporated and purified by silica gel column chromatography with the appropriate mixture of n-hexane and ethyl acetate to afford the alcohols, which are all known compounds. |
87% | With C18H32BrFeNO3P2; anhydrous sodium formate In methanol; dodecane at 40℃; for 6h; Inert atmosphere; chemoselective reaction; | |
86% | With potassium-t-butoxide; [(2,6-bis(phenylazo)pyridine)Ru(PMe2Ph)2(CH3CN)](ClO4)2; isopropanol at 82℃; for 6h; Inert atmosphere; chemoselective reaction; | |
85% | With formic acid; C18H14ClN4O2Ru(1+)*Cl(1-); anhydrous sodium formate In water monomer at 60℃; for 20h; Inert atmosphere; | |
84% | Stage #1: methyl 4-formylbenzoate With diphenylsilane; Cs2CO3 at 20℃; for 2h; Schlenk technique; Stage #2: With sodium hydroxide In methanol; water monomer at 70℃; Schlenk technique; chemoselective reaction; | |
83% | Stage #1: methyl 4-formylbenzoate With nickel(II) acetate tetrahydrate; tricyclohexylphosphine In tetrahydrofuran at 70℃; for 16h; Stage #2: With sodium hydroxide In methanol | |
80% | With 1,4-diaza-bicyclo[2.2.2]octane; anhydrous silver tetrafluoroborate; C15H4BClCoF18N6; hydrogen In tetrahydrofuran at 60℃; for 10h; | |
79% | With Mn(CO)<SUB>3</SUB>Br(k<SUP>2</SUP>P,N-Ph<SUB>2</SUB>PN(H)Py); hydrogen; 1,1,1,3,3,3-hexamethyldisilazane potassium In toluene at 50℃; for 20h; Glovebox; Autoclave; Inert atmosphere; | |
76% | With (2,6-dichlorophenyl)bis(2,3,5,6-tetrafluorophenyl)borane; hydrogen In tetrahydrofuran at 55℃; for 40h; | |
74% | With diludine; tris[3,5-bis(trifluoromethyl)phenyl]borane In 1,4-dioxane at 25℃; for 12h; Glovebox; | General procedure for the hydrogenation reaction General procedure: In a glovebox, aldehydes (0.25 mmol) and the Hantzsch ester 1 (95 mg, 0.38 mmol) were added to asolution of tris[3,5-bis(trifluoromethy)phenyl]borane (9) (8.1 mg, 12.5 μmol) in 1 mL of anhydrous1,4-dioxane. The reaction mixture was stirred at 25 or 100 C for 12 h. An internal standard (biphenylor mesitylene) was added to the reaction mixture and filtrated through a cotton plug. The resultingsolution was analyzed with gas chromatography. |
74% | Stage #1: methyl 4-formylbenzoate With chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II); phenylsilane In toluene for 2.5h; Reflux; Stage #2: With N,N,N-tributylbutan-1-aminium fluoride In toluene at 20℃; for 0.5h; chemoselective reaction; | 4.3. General procedure for the reduction of solid aldehydes with the system PhSiH3/[CpRu(PPh3)2Cl] General procedure: To a solution of [CpRu(PPh3)2Cl] (1 mol%) and solid aldehyde (1.0 mmol) in toluene (3 ml) was added PhSiH3 (1.2 mmol). The reaction mixture was stirred at reflux temperature under an air atmosphere (the reaction times are indicated in Table 4). Then, TBAF (1.0 mmol) was added and the reaction mixture was stirred at room temperature during 30 min. After evaporation, the reaction mixture was purified by silica gel column chromatography with ethyl acetate:n-hexane (1:3) to afford the corresponding alcohols. |
74% | With alpha-D-glucopyranose; bis[dichlorido(η5-1,2,3,4,5-pentamethyl-cyclopentadienyl)rhodium (III)]; anhydrous Sodium acetate In 1,2-dichloro-ethane at 120℃; for 24h; | |
66.5% | With hydrogen In ethanol at 50℃; Autoclave; | 1 Synthesis of methyl 4-(hydroxymethyl)benzoate Equipped with mechanical stirring 500ml hydrogenation autoclave was added methyl 4-formyl benzoate 51g, Raney-Ni 5g, anhydrous ethanol 200g, the pressure of hydrogen to 0.8MPa, closed to heat to 50°C (Autoclave pressure up to 1MPa), hydrogenation to no longer hydrogen absorption (about 5h) to stop the reaction. Raney-Ni was recovered by filtration, and the ethanol was recovered under reduced pressure to obtain a crude methyl 4-(hydroxymethyl)benzoate with a dry weight of 53g and a purity of 96.7% The crude yield is almost 100%. The crude product was distilled off under reduced pressure to give 34.3 g of a white solid The purity is 98.2%, the content of more than 98% of the product yield was 66.5%.The crude product can also be passed with more than 98% by recrystallization from hexane / ethyl acetate Methyl 4-(hydroxymethyl) benzoate product |
63% | Stage #1: methyl 4-formylbenzoate In water monomer at 50℃; for 1h; Inert atmosphere; Schlenk technique; Stage #2: With sodium cyanotrihydridoborate In water monomer at 50℃; for 6h; Inert atmosphere; Schlenk technique; Sealed tube; | |
55% | With diisobutylaluminum borohydride In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; | |
51% | Stage #1: methyl 4-formylbenzoate With Cp(CO)2Mn(IMes); diphenylsilane In toluene at 25℃; for 8h; Schlenk technique; Inert atmosphere; UV-irradiation; Stage #2: With sodium hydroxide In methanol; toluene at 20℃; for 2h; Schlenk technique; Inert atmosphere; | |
42% | With disodium sulphide; aluminum(III) oxide In n-heptane for 20h; Heating; | |
With hydrogen | ||
96 % Chromat. | With indium(III) trichloride; bis-tri-n-butylstannane In tetrahydrofuran at -78 - 25℃; for 1h; | |
With sodium tetrahydridoborate; Orthoboric acid for 0.0833333h; | ||
With anhydrous sodium formate; N-(2-amino-ethyl)-4-methyl-benzenesulphonamide at 80℃; for 0.6h; | ||
With sodium tetrahydridoborate In methanol at 20℃; for 1h; | ||
With sodium tetrahydridoborate | ||
With hydrogen In tetrahydrofuran at 60℃; for 18h; Autoclave; chemoselective reaction; | ||
With sodium tetrahydridoborate In ethanol UV-irradiation; chemoselective reaction; | ||
2.24 g | With sodium tetrahydridoborate In methanol at 0℃; for 2h; | Methyl 4-(hydroxymethyl)benzoate To a solution of methyl 4-formylbenzoate (4.00 g, 24.4 mmol) in CH3OH (40 mL) was addedNaBH4 (890 mg, 23.5 mmol) at 0 C. The reaction mixture was stirred at 0 C for 2 hours and thendissolved in water. The water phase was extracted three times with DCM and the combined DCMlayers were washed with brine, dried over MgSO4 and concentrated to give (2.24 g). 1H NMR(CDCl3, 400 MHz) 8.02 (d, 2H, J 8.4 Hz), 7.42 (d, 2H, J 8.8 Hz), 4.76 (d, 2H, J 6.0 Hz), 3.91 (s,3H), 1.97 (t, 1H, J 6.0 Hz). 13C NMR (CDCl3, 100 MHz) 167.1, 146.1, 130.0, 129.4, 126.6, 64.8,52.2. The spectral data was in accordance with previous reported values.5 |
97 %Chromat. | With methyl ammonia borane In water monomer at 20℃; for 0.5h; Green chemistry; chemoselective reaction; | General Procedure for the Hydrogenation of Carbonyl Compounds to Alcohols General procedure: A mixture of carbonyl compound (1 mmol) and MeAB (1 mmol) in neat water (2 mL) was stirred at room temperature for an appropriate time. The reaction was monitored by TLC and gas chromatography (GC). After completion, the reaction mixture was extracted with ethyl acetate (310 mL). Then, the organic extracts were concentrated by rotary evaporation, and the residue was purified by silica-gelcolumn chromatography (elution by using petroleum ether=ethyl acetate 5:1) to obtain the alcohol product. |
With sodium tetrahydridoborate; water monomer In acetonitrile | ||
79 %Chromat. | With sodium hydroxide In isopropanol at 82℃; for 0.75h; chemoselective reaction; | 2.3. Transfer hydrogenation of carbonyl compounds General procedure: In a typical procedure, a 5 mg (0.77 mol%) of RuO2/MWCNT and 80 mg (2 mmol) of NaOH were stirred with 5 mL of i-PrOH taken in an ace pressure tube equipped with a stirring bar. Then the substrate (1 mmol) was added to the stirring solution and then the mixture was heated at 82°C. The completion of the reaction was monitored by GC. After the reaction, the catalyst was separated out from the reaction mixture by simple centrifugation and the products and unconverted reactants were analyzed by GC without any purification. Selectivity of the product for each reaction was alsocalculated. Finally, the separated RuO2/MWCNT was washed well with diethyl ether followed by drying in an oven at 60°C for 5 h and it was reused for the subsequent transfer hydrogenation of carbonyl compounds to investigate the reusability of the RuO2/MWCNT. |
Stage #1: methyl 4-formylbenzoate With sodium tetrahydridoborate In tetrahydrofuran at -15℃; for 0.25h; Stage #2: In tetrahydrofuran; methanol at -15 - 20℃; for 1.5h; | ||
> 99 %Spectr. | With C36H103AlO4Si14; isopropanol In neat (no solvent) at 50℃; for 24h; Glovebox; Schlenk technique; | |
With sodium tetrahydridoborate In methanol | ||
75 %Spectr. | With C24H50B2N2P2Ru; hydrogen In tetrahydrofuran; dodecane at 180℃; for 21h; Inert atmosphere; Glovebox; | |
> 99 %Spectr. | With Au0998Ag0002; hydrogen; triethylamine at 90℃; for 24h; chemoselective reaction; | |
With sodium tetrahydridoborate Inert atmosphere; | ||
With sodium tetrahydridoborate at 0℃; | ||
With C24H37IrN2O2P2; C44H68Ir2N2O4P4; hydrogen In tetrahydrofuran at 21.84℃; for 20h; chemoselective reaction; | ||
Multi-step reaction with 2 steps 1: [CoCl2(4'-(4-pyridyl)-2,2':6',2''-terpyridine)]·2H2O; potassium-t-butoxide / tetrahydrofuran / 16 h / 25 °C / Inert atmosphere; Glovebox 2: mesoporous silica / 25 °C / Inert atmosphere; Glovebox | ||
With sodium tetrahydridoborate In methanol at 0 - 20℃; for 1h; | ||
With sodium tetrahydridoborate | ||
Multi-step reaction with 2 steps 1: C74H94Cu9N4O28 / neat (no solvent) / 1 h / 20 °C / Glovebox; Inert atmosphere 2: mesoporous silica / ethyl acetate; hexane / 20 °C | ||
Multi-step reaction with 2 steps 1: two-dimensional iron(II) coordination polymer based on a divergent 4'-(4-diphenylamino)phenyl-4,2';6',4''-terpyridine ligand; potassium-t-butoxide / neat (no solvent) / 4 h / 20 °C / Green chemistry 2: mesoporous silica / ethyl acetate; hexane / 20 °C | ||
With sodium tetrahydridoborate In methanol | ||
Multi-step reaction with 2 steps 1: C84H108Cl2N10Pd2 / neat (no solvent) / 12 h / 60 °C / Glovebox 2: mesoporous silica; methanol / 6 h / 60 °C | ||
Multi-step reaction with 2 steps 1: lithium bromide / tetrahydrofuran / 1 h / 24 - 25 °C / Inert atmosphere 2: sodium hydroxide; water monomer / tetrahydrofuran; water monomer / 1 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 0.55C27H43N3Si3V*0.45C27H44N3Si3V / diethyl ether / 2 h / 20 °C / Inert atmosphere; Glovebox; Schlenk technique 2: air / diethyl ether | ||
With formic acid; anhydrous sodium formate In water monomer at 80℃; for 2h; | ||
With hydrogen; potassium hydroxide In methanol at 40℃; for 1h; Autoclave; chemoselective reaction; | ||
With methanol; sodium tetrahydridoborate at 0℃; Schlenk technique; Cooling with ice; Inert atmosphere; | ||
98 %Spectr. | Stage #1: methyl 4-formylbenzoate With phenylsilane; C23H24N3Ni(1+)*Br(1-) In tetrahydrofuran at 40℃; for 4h; Schlenk technique; Inert atmosphere; Stage #2: With water monomer; sodium hydroxide In tetrahydrofuran; methanol at 25℃; for 2h; Schlenk technique; Inert atmosphere; | |
With methanol; sodium tetrahydridoborate at 20℃; for 2h; | ||
With sodium tetrahydridoborate In methanol at 0 - 20℃; for 3h; Inert atmosphere; | ||
With sodium tetrahydridoborate In methanol at 20℃; for 0.5h; | ||
1600 mg | With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 1h; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
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80% | Stage #1: Monomethyl terephthalate With trimethylphenylsilane; C69H55ClP3Ru In tetrahydrofuran at 60℃; for 16h; Glovebox; Stage #2: With hydrogenchloride In tetrahydrofuran; water monomer at 20℃; for 1h; Glovebox; chemoselective reaction; | |
75% | Stage #1: Monomethyl terephthalate With phenylsilane; potassium-t-butoxide; C22H30ClN2RuS2(1+)*Cl(1-) In tetrahydrofuran; 1,4-dioxane at 100℃; for 18h; Inert atmosphere; Stage #2: With water monomer; caesium fluoride In tert-butyl methyl ether at 20℃; for 3h; Inert atmosphere; chemoselective reaction; | 4-Hydroxymethyl-benzoic acid methyl ester (4a): To a stirred suspension of terephthalicacid monomethyl ester 3a (500mg, 2.7753 mmol, 1equiv.) in degassed 1,4-dioxane (10 V) was added ARP-03 (29.0mg, 0.0555 mmol, 2 mol%) and again degassed for 10 minutes. After 10 minutes ofdegassing, PhSiH3 (1.72 mL, 13.8765 mmol, 5 equiv.) and t-BuOK (1 Min THF) (0.28 mL, 0.2775 mmol, 10 mol%) were added dropwise to reaction mixtureat RT. The reaction mixture was heated to 100°C and stirred for 18 h. Thereaction mixture was then evaporated to remove volatiles, then suspended inMTBE and stirred with aq. CsF solution (10%, 10 V) for 3 h. The organic layerwas then separated and concentrated in vacuum to furnish the crude, which was purified by column chromatography on silica gel(eluent: Ethyl acetate / n-hexane = 1/4) to afford 4-hydroxymethyl-benzoic acidmethyl ester (4a) (345 mg, 75%) as acolourless oil.1H NMR (300 MHz, DMSO- d6): δ 7.92 (d, J = 8.1 Hz, 2H),7.46 (d, J = 8.1 Hz, 2H), 5.37 (t, J = 5.4 Hz, 1H), 4.58 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H).13C NMR (100 MHz, DEPT -135, CDCl3): δ 167.10 (CO), 146.10(C), 129.98 (CH×2), 129.46 (C), 126.60 (CH×2), 64.83 (CH2), 52.25(CH3).LCMS (EI, m/z) calcd for C8H10O3[M + H]: 167.18 Found: 167.1 |
72% | With Benzyltriethylammonium borohydride In dichloromethane Heating; |
67% | With C25H42N6Rh(1+)*CF3O3S(1-); phenylsilane In tetrahydrofuran at 30℃; for 20h; Inert atmosphere; | |
43% | With tributylphosphine; diphenylsilane; C45H25F12N7Ni2O9 In 1,4-dioxane at 100℃; for 16h; | |
Multi-step reaction with 2 steps 1: 79 percent / dicyclohexylcarbodi-imide / ethyl acetate / 24 h / Ambient temperature 2: 95 percent / NaBH4, H2O / tetrahydrofuran / 0.08 h / Ambient temperature | ||
With sodium borohydride; boron trifluoride-diethyl ether complex In tetrahydrofuran; water monomer | 1 Preparation of Methyl p-Hydroxymethylbenzoate (Me pHMB). EXAMPLE 1 Preparation of Methyl p-Hydroxymethylbenzoate (Me pHMB). To a stirred suspension of monomethylterephthalate (513.0 g., 2.85 moles) and sodium borohydride (94.0 g., 2.47 moles) in 4.0 liters of tetrahydrofuran, was added boron trifluoride etherate (465 g., 3.28 moles) at a rate to maintain a gentle reflux. The mixture was stirred for 2 hours at 20° C. Water (200 ml.) was added slowly, and the solvents were removed on a rotary evaporator. The residue was taken up in 3.5 liters of water and 1.5 liters of dichloromethane, the layers were separated, and the aqueous portion was extracted with dichloromethane (three 400 ml. portions). The combined organic portions were extracted with 2.5% sodium bicarbonate (1.0 liter), then dried over anhydrous sodium sulfate. Removal of solvent in vacuo left 466.5 g. (98.6%) Me pHMB; m.p. 47°-48° C. Distillation at 125°-127° C./0.4 torr and recrystallization from two parts carbon tetrachloride and one-half part hexane at 47° C. gave a purified product: m.p. 48.5°-49.5° C; ir (nujol) 3400-3200, 1725, 1290, 1115, 1050, 1020, and 760 cm.-1; nmr (CDCl3) 7.82 and 7.23 (AB quartet, JAB =9Hz, 4H), 4.58 (S, 2H), 3.80 (S, 3H), and 3.67 (broad S, 1H); mass spectrum m/e 166 (parent ion), 107 (base peak ion); acetylation gc, 99.91% Me pHMB. Analysis Calculated for C9 H10 O3: C, 65.1; H, 6.1; Found: C, 65.0; H, 6.2. | |
Multi-step reaction with 2 steps 1: (4-Me)Triaz(NHP<SUP>i</SUP>Pr<SUB>2</SUB>)<SUB>2</SUB>Mn(CO)<SUB>2</SUB>Br / toluene / 6 h / 25 °C / Inert atmosphere 2: mesoporous silica; water monomer / methanol / 60 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; chloro-trimethyl-silane In 1,4-dioxane at 20 - 25℃; for 6 - 7h; | 1; 7 Example 1; Artemisinin (1.0 g), polyhydroxy compound (dextrose, 5.0 g), sodium borohydride (2.0 g) and methyl p-(hydroxymethyl) benzoate (2.1 g) and chlorotrimethylsilane (CTMS) (1.0 ml) were stirred in 1,4-dioxan (40 ml) at room temperature at 25° C. for about 7 hrs. It was filtered. The filterate was further stirred with 10% KOH/H2O (75 ml) for about 2 hrs. The reaction mixture was neutralized with 5% CH3COOH, extracted with ethyl acetate (2×60 ml). The ethyl acetate extract was dried over anhydrous sodium sulphate and evaporation of solvent yielded impure artelinic acid (1.25 gm) which was recrystallized in ethyl acetate-hexane to yield pure artelinic acid in 98% yield (980 mg). After thorough drying the pure artelinic acid, m.p 142-415° C. was characterized by spectral analysis.; Example 7; Artemisinin (500 mg), PHC (dextrose, 3.0 g), sodium borohydride (1.0 g) and methyl p-(hydroxymethyl) benzoate (1.0 g) and chlorotrimethylsilane (CTMS) (0.5 ml) were stirred in 1,4-dioxan (15 ml) at room temperature (20° C.) for about 6.0 hrs. After completion of the reduction and alkylation reaction (Checked by TLC), 15% KOH/MeOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 2 hours at room temp. Added cooled water (50 ml) in the reaction mixture and the pH of the aqueous reaction mixture was adjusted about 6.0 with dilute acetic acid and extracted with 50% ethyl acetate in hexane (3×25 ml). The combined extract was washed with water (50 ml). The ethyl acetate n-hexane extract was dried over anhydrous sodium sulphate and evaporation of the solvent yielded 935 mg of crude artelinic acid which upon purification over silica gel column (1:5 ratio) with 15-25% ethyl acetate in hexane, furnished pure artelinic acid (380 mg) in 76% w/w yield. | |
With sodium tetrahydroborate; chloro-trimethyl-silane In 1,4-dioxane at 20 - 30℃; for 2.5 - 3h; | 5; 8; 9; 12 Example 5; Artemisinin (500 mg), cation exchange resin (5.0 g), sodium borohydride (1.0 g) and methyl p-(hydroxymethyl) benzoate (1.0 g) were stirred in 1,4-dioxan (10 ml) at room temperature at 25° C. for about 2.5 hours. After completion of the reduction and alkylation reaction (Checked by TLC) it was filtered. In the filtrate, 15% KOH/ EtOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for about 2 hrs at room temperature. Added cooled water (50 ml) in the reaction mixture and the pH of the aqueous reaction mixture was adjusted about 6.0 with dilute acitic acid and extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extract was dried over anhydrous sodium sulphate and evaporation of the solvent yielded 0.515 g of impure artelinic acid which upon recrystallization with mixture of ethyl acetate-hexane furnished pure artelinic acid (0.456 g) in 91.2% w/w yield.; Example 8 Artemisinin (500 mg), cation exchange resin (5.0 g), sodium borohydride (1.0 g) and methyl p-(hydroxymethyl) benzoate (1.0 g) were stirred in 1,4-dioxan (10 ml) at room temperature (27° C.) (20-30 degree C.) for about 2.5 hours. After completion of the reduction and alkylation reaction (Checked by TLC) 15% KOH/EtOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 2-2.5 hours at room temperature. Added cooled water (50 ml) in the reaction mixture and the pH of the aqueous reaction mixture was adjusted about 6.0 with dilute acetic acid and extracted with 50% ethyl acetate in hexane (3×25 ml). The combined extract was washed with water (50 ml). The ethyl acetate n-hexane extract was dried over anhydrous Sodium sulphate and evaporation of the solvent yielded 900 mg of crude artelinic acid which upon purification over silica gel column (1:5 ratio) with 15-25% ethyl acetate in hexane, furnished pure artelinic acid in 82% w/w yield. After drying the pure artelinic acid, m.p 142-415° C. was characterized by spectral analysis.; Example 9 Artemisinin (500 mg), cation exchange resin (5.0 g), sodium borohydride (1.5 g) and methyl p-(hydroxymethyl) benzoate (750 mg) were stirred in 1,4-dioxan (10 ml) at room temperature (30° C.) for about 3.0 hrs. After completion of the reduction and alkylation reaction (Checked by TLC ), 5% KOH/MeOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 24 hours at room temp. After usual work up and purification through column chromatography (1:4 ratio) yielded 150 mg (30%) pure artelinic acid.; Example 12 Artemisinin (2 g), cation exchange resin (20.0 g), sodium borohydride (5.0 g) and methyl p-(hydroxymethyl) benzoate (4.0 g) were stirred in 1,4-dioxan (60 ml) at room temperature (23° C.) for about 3.0 hrs. After completion of the reduction and alkylation reaction (Checked by TLC) 15% KOH/EtOH(40 ml) was added slowly at room temperature and the reaction mixture was stirred further for 2-2.5 hrs at room temperature. Added cooled water (50 ml) in the reaction mixture and the pH of the aqueous reaction mixture was adjusted about 6.0 with dilute acetic acid and extracted with 50% ethyl acetate in hexane (3×50 ml). The combined extract was washed with water (500 ml). The ethyl acetate n-hexane extract was dried over anhydrous sodium sulphate and evaporation of the solvent yielded 3.96 g of crude artelinic acid which upon purification over silica gel column (1:5 ratio) with 15-25% ethyl acetate in hexane, furnished pure artelinic acid in 85% w/w yield. | |
With sodium tetrahydroborate; chloro-trimethyl-silane In tetrahydrofuran at 20 - 30℃; for 2h; | 6; 10 Example 6; Artemisinin (500 mg), cation exchange resin (5.0 g), sodium borohydride (1.0 g) and methyl p-(hydroxymethyl) benzoate (1.0 g) were stirred in tetrahydrofuran (10 ml) at room temperature (27° C.) for about 2.0 hrs. After completion of the reduction and alkylation reaction, it was filtered. In the filtrate 10% KOH/MeOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 4 hrs at room temp. After usual work up and purification through recrystallization yielded 235 mg (47%) pure artelinic acid.; Example 10 Artemisinin (500 mg), cation exchange resin (5.0 g), sodium borohydride (1.0 g) and methyl p-(hydroxymethyl) benzoate (1.0 g) were stirred in tetrahydrofuran (10 ml) at room temperature (23° C.) (20-30 degree C.) for about 2.0 hrs. After completion of the reduction and alkylation reaction (Checked by TLC), 5% KOH/MeOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 24 hours at room temp. After usual work up and purification through column chromatography (1:4 ratio) yielded 100 mg (20%) pure artelinic acid. |
With sodium tetrahydroborate; chloro-trimethyl-silane In 1,4-dioxane at 23℃; for 8h; | 4 Example 4; Artemisinin (50 mg), PHC (galactose, 300 mg), sodium borohydride (150 mg) and methyl p-(hydroxymethyl) benzoate (150 mg) and chlorotrimethylsilane (CTMS) (0.2 ml) were stirred in dioxane (3 ml) at room temperature at 23° C. for about 8.0 hrs. The reaction mixture was filtered. In the filtrate, 5% KOH/EtOH (15 ml) was added slowly at room temperature and it was stirred further for 7 hours at room temp. After usual work up and purification through prep TLC, yielded 9 mg (18%) artelinic acid. | |
With sodium tetrahydroborate; chloro-trimethyl-silane In tetrahydrofuran at 25℃; for 8h; | 3 Example 3; Artemisinin (50 mg), phloroglucinol (300 mg), sodium borohydride (150 mg) and methyl p-(hydroxymethyl) benzoate (150 mg) and chlorotrimethylsilane (CTMS) (0.05 ml) were stirred in tetrahydrofuran (4 ml) at room temperature at 25° C. for about 8.0 hrs. The reaction mixture was filtered. In the filtrate 10% KOH/MeOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 3 hours at room temp. After usual work up and purification through prep TLC yielded 11 mg (22%) pure artelinic acid. | |
With sodium tetrahydroborate; chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 8h; | 2 Example 2; Artemisinin (50 mg), PHC (dextrose, 250 mg), sodium borohydride (100 mg) and methyl p-(hydroxymethyl) benzoate (100 mg) and chlorotrimethylsilane (CTMS) (0.1 ml) were stirred in tetrahydrofuran (3 ml) at room temperature at 20° C. for about 8.0 hrs. After completion of the reduction and alkylation reaction it was filtered. In the filtrate, 10% KOH/MeOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 3.5 hours at room temp. After usual work up and purification through prep TLC, yielded 16 mg (32%) artelinic acid. | |
With sodium tetrahydroborate; chloro-trimethyl-silane In tetrahydrofuran at 30℃; for 4h; | 11 Example 11; Artemisinin (50 mg), PHC (100 mg), sodium borohydride (1.0 g) and methyl p-(hydroxymethyl) benzoate (1.0 g) were stirred in tetrahydrofuran (3 ml) at room temperature (30° C.) for about 4.0 hrs. 5% KOH/MeOH (15 ml) was added slowly at room temperature and the reaction mixture was stirred further for 24 hours at room temp. After usual work up and purification through prep TLC, yielded 4 mg (8%) artelinic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dichloro(benzene)ruthenium(II) dimer; 2-((di-p-tolylphosphino)methyl)-1-methyl-1H-imidazole; potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran at 100℃; for 4.5h; | |
76% | Stage #1: 4-(methoxycarbonyl)benzyl alcohol With diethoxymethylane; sodium triethylborohydride In diethyl ether; toluene at 20℃; for 8h; Inert atmosphere; Stage #2: With sodium hydroxide In methanol; diethyl ether; toluene at 20℃; for 2h; | |
63% | With [RuCl2(N-heterocyclic carbene)(bis[2-(diphenylphosphino)ethyl]amine)]; potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran; 2-methyltetrahydrofuran at 45℃; for 2.5h; Autoclave; |
Multi-step reaction with 4 steps 1: 100 percent 2: 88 percent / LiAlH4 / diethyl ether; diethyl ether / 1 h / Heating 3: 87 percent 4: 17 percent / 31percent aq. H2SiF6, Et3N / acetonitrile / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | D Methyl 4-(Methanesulfonylmethyl)benzoate Part D Methyl 4-(Methanesulfonylmethyl)benzoate A solution of methyl 4-(hydroxymethyl)benzoate (10.8 g, 0.065 mol) and proton sponge (19.5 g, 0.091 mol) in DCM (200 ml) was treated with methanesulfonic anhydride (13.94 g, 0.08 mol) and stirred at room temperature for 20 hours. The reaction mixture was washed with 100 ml portions of H2 O (1*), 1N HCl (2*), H2 O (1*), saturated NaHCO3 (1*), and H2 O (1*). The organic phase was dried (MgSO4) and concentrated to give 15.5 g of pale yellow solid. Recrystallization from CCl4 (150 ml) using decolorizing carbon gave product (14.2 g, 90%) as colorless needles, MP 91°-94° C. |
90% | With hydrogenchloride In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | 9.D Part D Part D Preparation of Methyl 4-(Methanesulfonylmethyl)benzoate A solution of methyl 4-(hydroxymethyl)benzoate (10.8 g, 0.065 mol) and proton sponge (19.5 g, 0.091 mol) in DCM (200 ml) was treated with methanesulfonic anhydride (13.94 g, 0.08 mol) and stirred at room temperature for 20 hours. The reaction mixture was washed with 100 ml portions of H2O (1*), 1N HCl (2*), H2O (1*), saturated NaHCO3 (1*), and H2O (1*). The organic phase was dried (MgSO4) and concentrated to give 15.5 g of pale yellow solid. Recrystallization from CCl4 (150 ml) using decolorizing carbon gave product (14.2 g, 90%) as colorless needles, MP 91-94° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; acetonitrile; | Referential Example 56 Methyl 4-cyanomethylbenzoate In dichloromethane (20 ml), methyl 4-hydroxymethylbenzoate (1.00 g) was dissolved, followed by the addition of triethylamine (0.9 ml). Under ice cooling, a solution of methanesulfonyl chloride (0.70 g) in dichloromethane (dichloromethane: 5 ml) was added to the resulting solution. The resulting mixture was stirred at room temperature for 15 hours. After dilution with dichloromethane, the reaction mixture was washed with water and was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in acetonitrile (12 ml). To the resulting solution, potassium cyanide (0.80 g) and 18-Crown-6 (0.16 g) were added, followed by stirring at room temperature for 40 hours. After concentration under reduced pressure, the concentrate was diluted with dichloromethane, washed with water and then, dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane), whereby colorless crystals (0.91 g, 86%) was obtained. A portion of the resulting crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained. 1H-NMR (CDCl3) delta: 3.82(2H,s), 3.93(3H,s), 7.42(2H,d,=8.3 Hz), 8.06(2H,d,J=8.3 Hz). | |
With triethylamine; In dichloromethane; acetonitrile; | [Referential Example 56] Methyl 4-cyanomethylbenzoate In dichloromethane (20 ml), methyl 4-hydroxymethylbenzoate (1.00 g) was dissolved, followed by the addition of triethylamine (0.9 ml). Under ice cooling, a solution of methanesulfonyl chloride (0.70 g) in dichloromethane (dichloromethane: 5 ml) was added to the resulting solution. The resulting mixture was stirred at room temperature for 15 hours. After dilution with dichloromethane, the reaction mixture was washed with water and was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in acetonitrile (12 ml). To the resulting solution, potassium cyanide (0.80 g) and 18-Crown-6 (0.16 g) were added, followed by stirring at room temperature for 40 hours. After concentration under reduced pressure,the concentrate was diluted with dichloromethane, washed with water and then, dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane), whereby colorless crystals (0.91 g, 86%) was obtained. A portion of the resulting crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained. 1H-NMR (CDCl3) delta: 3.82(2H,s), 3.93(3H,s), 7.42(2H,d,=8.3Hz), 8.06(2H,d,J=8.3Hz). Elementary analysis for C10H9NO2 Calculated: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.39; H, 5.29; N, 8.08. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In toluene at 75℃; for 1.5h; | 3 INTERMEDIATE 3; METHYL 4-[(3-CHLOROISOQUINOLIN-l-YL)OXY]METHYL}BENZOATE EPO A toluene (3mL) solution containing 1,3-dichloroisoquinoline (50mg, 0.25mmol), 4- (hydroxymethyl)benzoate (105mg, 0.63mmol), cesium carbonate (206rng,0.63mmol), palladium acetate (5mg, 0.02mmol) and racemic-2-(di-t-butylphosphino)-l,r-binaphthyl (14mg, 0.035mmol) was heated at 750C for 1.5 hours. The solution was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using hexanes/ethyl acetate gradient. 1H NMR (500 MHz, CDCl3): δ 8.30 (d, J = 8.3 Hz, 1 H); 8.13 (d, J = 8.3 Hz, 2 H); 7.72-7.70 (m, 2 H); 7.65 (d, J = 8.2 Hz, 2 H); 7.59-7.55 (m, 1 H); 7.34 (s, 1 H); 5.68 (s, 2 H); 3.98 (s, 3 H). LCMS2 2.73min. (M+H)=328 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With oxone||potassium monopersulfate triple salt; 2-iodo-N-isopropyl-5-methoxybenzamide; tetra(n-butyl)ammonium hydrogensulfate In nitromethane; water at 25℃; for 16h; Green chemistry; | Typical experimental procedure for oxidation of primary alcohols 14g-k [7] General procedure: Primary alcohol 14 (0.50 mmol) was added to a solution of the catalyst (0.15 mmol) and Bu4NHSO4 (170 mg, 0.50mmol) in a mixture of MeNO2 (1.6 mL) and water (0.6 mL), followed by Oxone (768 mg. 1.25 mmol) at room temperature (25 °C). After 14 were completely consumed as indicated by TLC, the resulting mixture was diluted with EtOAc, water, and saturated aqueous Na2S2O3. The organic layer was then washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine; dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the catalyst. The combined aqueous layers were acidified with 10% HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give pure carboxylic acid 26. All carboxylic acids 26 were directly identified by comparison with the commercial samples. |
94% | With diethylene glycol dimethyl ether at 70℃; for 0.5h; Sonication; | 30 Example 30: Preparation of monomethyl terephthalate: In a 10 mL round bottom flask, 0.83 g of methyl 4-(hydroxymethyl)benzoate and 2 g of diethylene glycol dimethyl ether were added in sequence.The resulting mixture is in an ultrasonic reaction device,40KHz/30W/70°C ultrasonic radiation was opened for 30 minutes.The diethylene glycol dimethyl ether was removed under reduced pressure, and recrystallized to obtain 0.85 g of monomethyl terephthalate in a yield of 94%. |
91% | With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium chloride; oxygen In 1,2-dichloro-ethane at 25℃; for 48h; Schlenk technique; | General procedure: To a Schlenk tube were added Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol), TEMPO (15.8 mg, 0.1 mmol), KCl (7.5 mg, 0.1 mmol), 1a (108.5 mg, 1.0 mmol), and DCE (4.0 mL) sequentially under an atmosphere of oxygen (gas bag, commercial size: 2 L, which could be expanded to 5 L). The mixture was then stirred at 25 °C until completion of the reaction as monitored by TLC (petroleum ether/EtOAc = 5:1) (48h). The crude reaction mixture was filtered through a short column of silica gel (height: 2 cm, diameter: 3 cm) eluting with Et2O (3 × 25 mL). After evaporation, the residue was purified by chromatography on silica gel [petroleum ether/EtOAc = 15:1 (500 mL) to 2:1 (300 mL)] to afford benzoic acid (2a)14 (69.9 mg, 57%) as a pale yellow solid. Yields of 57% of 2a and 38% of benzaldehyde (3a)15 were observed by NMR analysisof the crude product using CH2Br2 as an internal standard and by comparison with spectra reported in the literature. |
85% | With oxygen at 120℃; for 16h; Green chemistry; | |
83% | With oxygen In water; <i>tert</i>-butyl alcohol at 100℃; for 0.533333h; Flow reactor; Green chemistry; | |
94.6 g (94%) | With sulfuric acid In water; acetone | 84.a a. a. 4Methoxycarbonylbenzenecarboxylic acid Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liter). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218°-221° C. |
94.6 g (94%) | With sulfuric acid In water; acetone | 14.a a. a. 4-Methoxycarbonylbenzenecarboxylic acid or 1,4-benzenedicarboxylic acid monomethyl ester Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liters). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the compound as white crystals, m.p. 218°-221° C. |
With sulfuric acid In water; acetone | 11.a a. a. 4-Methoxycarbonylbenzenecarboxylic acid or 1,4-benzenedicarboxylic acid monomethyl ester Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liters). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218°-221° C. STR51 Using the method of Example 6c, a product prepared according to Example 11a was allowed to react with the product prepared according to Example 3d to afford the final productproduct (83%); TLC, Rf =0.45, silica gel, CHCl3:MeOH (95:5). | |
77 %Chromat. | With sodium hypochlorite In 1,2-dimethoxyethane; water at 20℃; | |
81 %Chromat. | With [2,2]bipyridinyl; Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; acetic acid at 80℃; for 4h; | |
94.6 g (94%) | With sulfuric acid In water; acetone | 8.a a. a. 4-Methoxycarbonylbenzenecarboxylic acid. Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution of added dropwise over 1 hr to a stirred solution was methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 l). The precipitate which formed was collected, washed three times with water (1 l), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218-221°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | 9.D Part D Part D Preparation of Methyl 4-(Methanesulfonylmethyl)benzoate A solution of methyl 4-(hydroxymethyl)benzoate (10.8 g, 0.065 mol) and proton sponge (19.5 g, 0.091 mol) in DCM (200 ml) was treated with methanesulfonic anhydride (13.94 g, 0.08 mol) and stirred at room temperature for 20 hours. The reaction mixture was washed with 100 ml portions of H2O (1X), 1N HCl (2X), H2O (1X), saturated NaHCO3(1X), and H2O (1X). The organic phase was dried (MgSO4) and concentrated to give 15.5 g of pale yellow solid. Recrystallization from CCl4(150 ml) using decolorizing carbon gave product (14.2 g, 90%) as colorless needles, MP 91-94°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.06 g (63%) | In dichloromethane | 1 Experiment 1.8 Synthesis of 4-[(2-Cyanoethyl)(diisopropylamino)phosphanyloxymethyl]-benzoic Acid Methyl Ester, Compound11 (a) Experiment 1.8 Synthesis of 4-[(2-Cyanoethyl)(diisopropylamino)phosphanyloxymethyl]-benzoic Acid Methyl Ester, Compound11 (a) To a solution of 3.73 (22 mmol) of 4-hydroxymethylbenzoic acid methyl ester (10) and 0.16 g (2.2 mmol) of tetrazol in 50 ml of dichloromethane was added a solution of 7.4 g (24.6 mmol) of bis-(diisopropylamino)-(2-cyanoethoxy)-phosphine in 20 ml of dichloromethane over 20 minutes. Upon complete addition, the mixture was stirred for 1.5 hour at rt, concentrated, and chromatographed (heptane/ethyl acetate 4/1 with trace triethylamine) to afford 5.06 g (63%) of 11: 1H-NMR 8.1 (m, 2H), 7.5 (m, 2H), 4.8 (m, 2H), 3.9 (s, 3H), 3.8 (m, 2H), 3.7 (m, 2H), 1.1 (m, 12H), 31P-NMR 149.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 1-methyl-piperazine With formic acid for 0.25h; cooling; Stage #2: methyl 4-formylbenzoate at 180 - 200℃; for 8h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: oct-1-en-3-yl acetate With (S)-((4,4’-bi-1,3-benzodioxole)-5,5’-diyl)bis(diphenylphosphine); bis(1,5-cyclooctadiene)diiridium(I) dichloride; 2-nitro-4-carboxybenzonitrile; caesium carbonate In tetrahydrofuran at 90℃; for 0.5h; Inert atmosphere; Stage #2: 4-(methoxycarbonyl)benzyl alcohol In tetrahydrofuran at 90℃; for 48h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: oct-1-en-3-yl acetate With bis(1,5-cyclooctadiene)diiridium(I) dichloride; 2-nitro-4-carboxybenzonitrile; caesium carbonate; 2,2'-bis(diphenylphosphino)biphenyl In tetrahydrofuran at 90℃; for 0.5h; Inert atmosphere; Stage #2: 4-(methoxycarbonyl)benzyl alcohol In tetrahydrofuran at 90℃; for 48h; Inert atmosphere; optical yield given as %de; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Methyl 4-hydroxymethylbenzoate (1.00 g) was dissolved in dichloromethane (20 ml). After addition of triethylamine (0.9 ml) to the resulting solution, a dichloromethane solution (dichloromethane: 5 ml) of methanesulfonyl chloride (0.70 g) was added under ice cooling. After stirring at room temperature for 15 hours, the reaction mixture was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in acetonitrile (12 ml). Potassium cyanide (0.80 g) and 18-crown-6 (0.16 g) were added and the resulting mixture was stirred at room temperature for 40 hours. After concentration of the reaction mixture under reduced pressure, the residue was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (dichloromethane) on a silica gel column, whereby colorless crystals (0.91 g, 86%) were obtained. A portion of the crystals were recrystallized from a mixed solvent of hexane and ethyl acetate to yield colorless crystals.1H-NMR (CDCl3) delta: 3.82(2H,s), 3.93(3H,s), 7.42(2H,d,J=8.3Hz), 8.06(2H,d,J=8.3Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With oxygen; potassium carbonate In methanol at 60℃; for 20h; | 2.7 Aerobic oxidative esterification of benzyl alcohol for comparison of catalysts General procedure: A mixture of benzyl alcohol (108mg, 1mmol),K2CO3 (138mg, 1mmol), and catalysts (0.005mmol, 0.5mol% on the total metal basis) in dry methanol (2ml) was prepared in a reaction tube at room temperature. The reactor was then purged and filled with pure oxygen (filled balloon). The resulting mixture was then stirred at 60°C under an oxygen atmosphere (balloon) for 1h. After completion of the reaction, the solid catalyst was filtered off and washed with methanol (2ml×3). The filtrate was combined and analyzed by GC (Hewlett-Packard 5890 GC equipped with HP-5 column) using anisole as the internal standard. |
83% | With bis(cyclopentadienyl)titanium dichloride; manganese In tetrahydrofuran for 0.916667h; Inert atmosphere; Reflux; | |
Multi-step reaction with 6 steps 1.1: triethylamine / acetonitrile / 0 - 20 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.08 h / 20 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 20 °C / Inert atmosphere 4.1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / acetonitrile / 0.25 h / 20 °C / Inert atmosphere 4.2: 20 °C / Inert atmosphere 5.1: toluene-4-sulfonic acid / methanol / 1 h / 20 °C / Inert atmosphere 6.1: palladium diacetate; ammonium formate / water / 20 °C / Inert atmosphere |
71 %Chromat. | With hydrogen In ethanol at 80℃; for 5h; Inert atmosphere; | |
63 %Chromat. | With 2,4,6-trimethyl-pyridine; 4,4'-dimethoxyphenyl disulfide; iridium(lll) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate; triphenylphosphine In toluene for 24h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With carbon tetrabromide; oxygen at 20℃; for 20h; Irradiation; | General procedure: Typical procedure: A solution of 4-tert-butylbenzyl alcohol (1a, 0.3 mmol) and CBr4 (0.09 mmol) in dry MeOH (4 mL) in a pyrex test tube, purged with an O2-balloon, was stirred and irradiated externally with four 22 W fluorescent lamps for 20 h. The reaction mixture was concentrated in vacuo. Purification of the crude product by PTLC (toluene) provided methyl 4-tert-butylbenzoate (2a) (Rf = 0.40, 54.0 mg, 94%). |
84% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; benzyl chloride In tetrahydrofuran at 65 - 70℃; for 20h; Inert atmosphere; Schlenk technique; | |
69% | With bismuth(lll) trifluoromethanesulfonate; dichloro bis(acetonitrile) palladium(II); oxygen; potassium carbonate at 60℃; for 3h; Schlenk technique; | 3.16 4.2.1 General procedure for the synthesis of 2 in Table2 General procedure: To a 25-mL Schlenk tube equipped with a magnetic stirrer, PdCl2(CH3CN)2 (0.05mol, 5mol%), Bi(OTf)3 (0.05mol, 5mol%), K2CO3 (1mmol) were added. Substrates 1 (1mmol) and MeOH (2mL) were added subsequently. The reaction tube was vacuumed and backfilled with oxygen (3 times). Then the reaction mixture was stirred at 60°C for 3h in the presence of an oxygen balloon. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Subsequently, the combined organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography with hexane/ethyl acetate to afford the corresponding products 2. |
60% | With dichloro bis(acetonitrile) palladium(II); silver tetrafluoroborate; oxygen; sodium t-butanolate at 45℃; Cooling with ice; | |
58% | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; (2-((2-(diphenylphosphanyl)ethyl)(quinolin-2-ylmethyl)amino)ethyl)diphenylphosphine oxide; potassium carbonate In n-heptane at 120℃; for 16h; | |
91 %Chromat. | With oxygen; potassium carbonate at 60℃; for 24h; Schlenk technique; Green chemistry; | |
> 99 %Chromat. | With carbon-nitrogen embedded cobalt nanoparticles (800); air In hexane at 25℃; for 96h; | |
65 %Chromat. | With oxygen; potassium carbonate at 70℃; for 5h; Autoclave; | |
85 %Chromat. | With potassium carbonate at 55℃; for 24h; | S6. Procedure for the synthesis of esters General procedure: A magnetic stir bar and the alcohol substrate were transferred to 20 mL glass tube and then 2 mL of MeOH oralcohol was added. Then, 35 mg catalyst and 10 mol% of K2CO3 were added. The glass tube containingreaction mixture was fitted with septum and connected to a balloon containing one bar air. Then the glass tubewas placed into a preheated aluminum block at 60°C. Temperature inside the reaction tube was measured tobe 55 oC and this temperature has been taken as the reaction temperature. After completion of the reaction,the glass tube was cooled down to room temperature. Af terwards, the catalyst was f iltered-off and washedwith methanol. The solvent from the filtrate containing the reaction products was removed in vacuum and thecorresponding ester was purified by column chromatography. Products were analyzed by GC-MS and NMRspectroscopy analysis. In the case of yields determined the by GC, 100 μL n-hexadecane was added to thereaction vial containing the products and diluted with ethyl acetate. Then catalyst was f iltered through a plugof silica and the filtrate containing product was analyzed by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With (carbonyl)chloro(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-Amyl alcohol; at 130℃; for 20h;Inert atmosphere; Cooling; | Example 6Direct Single-Stage Amination of Alcohols andHydroxy Acids by Means of Ammonia Over aHomogeneous Ruthenium Catalyst and Xantphos ata high V7J Vgas (according to the invention)Under an argon atmosphere, m g of starting material, mRU g of [carbonylchlorohydridotris(triphenylphosphane)ruthenium(II)] and mp g of 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene as catalyst and V07 ml of 2-methyl-2-butanol as solvent were introduced into a 50 mlsteel tube. The vessel was closed, pressurized three times with 20 bar of argon and depressurized each time. The vessel was then cooled by means of dry ice and m g of ammonia were condensed in. The reactor is heated to T C. and maintained at this temperature for 20 hours. Afier cooling to room temperature, the reactor was depressurized and opened, the solvent was removed on a rotary evaporator and the residue was dissolved in methanol and then analysed by gas chromatography. Reaction parameters and conversions and selectivities to the desired reaction product are shown in Tab. 5. The results show that many different hydroxy-thnctionalized substrates can be aminated by the method described. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrazine hydrate; In ethanol; for 20.0h;Reflux; | Step 2. Synthesis of 4-(hydroxymethyl)benzohydrazideA solution of methyl 4-(hydroxymethyl)benzoate (6.6 g, 40 mmol) and hydrazine hydrate (6 mL) in ethanol (30 mL) was stirred at reflux for 20 hours. The reaction mixture was concentrated to half volume through atmospheric pressure distillation. The solid was collected by filtration and washed with cold ethanol (2×10 mL). The filtrate was further concentrated and a second crop was similarly obtained and combined. The 4-(hydroxymethyl)benzohydrazide was obtained as a white solid (6.1 g, 93%). 400 MHz 1H NMR (DMSO-d6) delta: 9.68 (s, 1H), 7.75 (dd, J=6.4, 1.6 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.25 (t, J=6.0 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.43 (s, 2H). |
77% | With hydrazine hydrate; In ethanol; at 80℃; | To a stirred solution of methyl 4-(hydroxymethyl)benzoate (4.0 g, 24.07 mmol) in EtOH (40 mL) NH2NH2 H20 (12 mL, 240.70 mmol) was added and the resulting mixture was stirred overnight at 80 C. Completion of the reaction was monitored by TLC and the reaction mixture was' concentrated under vacuum. The resulting crude product was purified by flash chromatography (Eluent: 5-7% MeOH in DCM) to afford the title compound. Yield: 77% (3.1 g, off white solid). 1H NMR (400 MHz, DMSO-de): d 9.72 (s, 1 H), 7.79 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 5.30 (s, 1 H), 4.54 (s, 2H), 4.47 (s, 2H). LCMS: (Method A) 167.1 (M+H), Rt. 0.52 min, 99.77% (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium hexamethylsilazane; In N,N-dimethyl-formamide; toluene; at 70℃; for 2h; | To a solution of methyl 4-(hydroxymethyl)benzoate (500 mg, 3.0 mmol) and 2-bromoethyl ethyl ether (2.0 mL, 18 mmol) in dry DMF (25 mL) was added dropwise KHMDS (18 mL, 0.5 M in toluene, 9.0 mmol). After being stirred at 70 C was 2 h the mixture was treated with water and extracted with CH2Cl2. The combined organic layers were washed with brine and dried over MgSO4. After evaporation the crude product was purified by flash chromatography (hexane/EtOAc 5:1) to give 10a in 49% yield (350 mg). EI-MS: m/z 238 (M+); 1H NMR: (CDCl3, 600 MHz) delta (ppm): 1.23 (t, J = 7.0 Hz, 3H), 3.55 (q, J = 7.0 Hz, 2H), 3.61-3.67 (m, 4H), 3.91 (s, 3H), 4.64 (s, 2H), 7.42 (m, 2H), 8.01 (m, 2H); 13C NMR: (CDCl3, 90 MHz) delta (ppm): 15.2, 52.0, 66.7, 69.9, 69.9, 72.6, 127.2, 129.3, 129.7, 143.7, 167.0; IR: (NaCl) nu (cm-1): 2868, 1692, 1426, 1292, 1119, 764. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 5% 2: 76% 3: 10% | With cadmium(II) sulphide In acetonitrile at 20℃; for 24h; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: With tributylphosphine; diamide In benzene at 0℃; for 0.25h; Inert atmosphere; Stage #2: 2-monochlorophenol; 4-(methoxycarbonyl)benzyl alcohol In benzene at 0 - 23℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 67% 2: 13% | With dichloro(benzene)ruthenium(II) dimer; 2-((di-p-tolylphosphino)methyl)-1-methyl-1H-imidazole; potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran at 100℃; for 4.5h; | |
With dichlorido-bis[(2-diphenylphosphino)ethyl]amine-cobalt(II); hydrogen; sodium methylate In 1,4-dioxane at 120℃; for 48h; Autoclave; | ||
1: 9 %Spectr. 2: 88 %Spectr. | With tris((2-(diphenylphosphino)ethyl)amino)ruthenium monocarbonyl; hydrogen; phenol In toluene for 18h; Glovebox; Inert atmosphere; Heating; Autoclave; | II.II.8 II.8 Base-Free Hydrogenation of Esters (Dimethyl terephthalate) with phenol as activator In a dry argon filled glove box, a stainless steel autoclave was charged with the catalyst Ru(L)CO (I) (0.02 mmol), and phenol (0.04 mmol) and toluene (12 mL). The mixture was stirred for 30 min at RT. Then dimethyl terephthalate (3 mmol) was added. The argon atmosphere in the autoclave was replaced with H2 by twice pressurization to 30 bar, and pressure release at room temperature. The autoclave was then pressurized with H2 gas (60 bar). The solution was heated at 130 °C (heating mantel temperature) with stirring for 18 hrs. After cooling to 0 °C, the system was vented carefully and purged for 1 minute with argon. The conversion of starting ma- terial was analyzed by GC-MS, using an Agilent Technologies 6890N gas chromatography sys- tem coupled with an Agilent Technologies 5975B mass spectrometer and equipped with an Ag- ilent Technologies HP-5MS capillary column (30 m x 0.250 mm / 0.25 pm). The solution was then evaporated under vacuum to remove all volatiles, and a sample was measured by 1H-NMR in methanol-c^ with 1 ,1 ,2,2-tetrachloroethane as internal standard. 88 % yield of NP1 was ob- tained with a ratio of: 10/1/0.4 of the components NP1 : BDM : DMT respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate In toluene; benzene | (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(4-(methoxycarbonyl)-benzyloxy)phenyl)propanoic acid (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(4-(methoxycarbonyl)-benzyloxy)phenyl)propanoic acid (S)-cert-Butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxyphenyl)pro-panoate (100 mg, 218 μmol), triphenylphosphine (TPP, 171 mg, 653 μmol) and methyl 4-(hydroxymethyl)benzoate (80 mg, 479 μmol) were combined in 4 ml of dry benzene under nitrogen. A solution of DEAD (40% in toluene, 299 μl, 653 μmol), diluted with 3 ml of dry benzene, was added dropwise over 20 min at 4° C. The mixture was stirred 20 min at 4° C., then at rt overnight. The addition of TPP (57 mg, 218 μmol) and DEAD (100 μl, 218 μmol) was repeated twice to drive the reaction to completion. Volatiles were removed in vacuo and the crude material was purified by flash chromatography on silica gel (hexane/ethylacetate 95/5 to 1/1) afforded 60 mg (S)-2-(Fmoc-amino)-((4-methoxycarbonyl)benzyl)tyrosine tert-butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 85% 2: 97% | With per-rhenic acid In toluene for 24h; Reflux; | General procedure: In a typical experiment, to a solution of HReO4 (5.0 mol %) in toluene (3 mL) was added the 4-methylphenyl sulfoxide (1.0 mmol) and the alcohol (1.0 mmol). The reaction mixture was heated at reflux temperature under air atmosphere (the reaction times are indicated in the Tables 1-3) and the progress of the reactions was monitored by TLC or 1H NMR. Upon completion, the reaction mixture was evaporated and purified by silica gel column chromatography with n-hexane to afford the carbonyl compounds and 4-methylphenyl sulfide, which are all known compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Stage #1: (R)-(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(3-(2,5-dichloro-4-hydroxybenzyl)thiazolidin-4-yl)methanone; 4-(methoxycarbonyl)benzyl alcohol With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃; for 16h; Stage #2: With lithium hydroxide monohydrate; water In 1,4-dioxane at 20℃; for 2h; Stage #3: 1-Amino-1-deoxy-D-glucitol; trifluoroacetic acid Further stages; | 176 Example 176: 4-(2,5-dichloro-4- { [(4R)-4-[(4-cyclopropyl- 1 ,2,3,4- tetrahydroquinoxalin- 1 -yi)carbonyl]~ l. ,3-thi.azolidtn-3-yl]methyl}phenoxymethyi)-N- [(2S,3R,4 ,5R)-2,3.4,5.6-pentahydroxyhexyl]benzamide Example 162 (172 mg, 0.370 mmol), methyl 4-(hydroxymethyl)benzoie acid (77 mg, 0.46 mmol), and tripheayphosphine (121 mg, 0.46 mmol) in DCM (3 mL) at 0 °C was added diisopropyl azodicarboxylate (91 ,uL, 0.46 mmol) and the mixture was allowed to warm to room temperature and then stirred for 16 h. The solvent was removed and the residue dissolved in a. mixture of H20 (5 mL) and 1 ,4-dioxane (25 mL). To this was added LiOH*H20 (62 mg, 1.5 mmol) and the mixture stirred at room temperature for 2 h. The solvent was removed, the residue dissolved in DCM and then washed with 1M aqueous HC1. dried over Na2S04, then filtered and concentrated. To a portion of the crude residue (-0.123 mmol), D-grucamine (42 mg, 0.23 mmol), and DiEA (128 jiL, 0.740 mmol) in DMF (2 mL) was added HATU (70 mg, 0.19 mmol) and the reaction stirred for 1 h. The mixture was diluted with j0, acidified with TFA, and. then purified by preparative HPLC with a C18 silica gel stationary phase using a gradient of 0 0.05% TFA : CH3CN 0.05% TFA (70 : 30 to 5 : 95) and detection by UV at 254 ran to give the title compound (21 mg, 17%) as a bis-TFA salt. MS (ES, m/z): 761.34 [M + Hf; NMR (400 MHz, CD3OD) δ 7.88 (d, J = 8.0 Hz, 2H), 7.58 (cl, J = 7.1 Hz, 2H), 7.25 is, 1 H), 7.20 (dd, J = 8.3, 1.3 Hz, 1.H), 7.17 - 7.08 (m, 2H), 7.08 - 6.99 (m, 1H), 6.67 (t, J - 7.2 Hz, 1 H), 5.25 (s, 2H), 4.80 - 4.72 (m, IH), 4.29 (d, J - 9.9 Hz, 1H), 4.14 - 3.86 (in, 4H), 3.86 -3.76 (m, 3H), 3.76 - 3.61 (m, 5H), 3.61 - 3.51 (m, IH), 3.47 (dd, J - 13.7, 7.3 Hz, i l l). 3.43 - 3.35 (m, 1 H), 3.21 - 3.09 (m, 2H), 2.44 (s, IH), 0.80 (s, 2H), 0.56 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tert.-butylhydroperoxide; water; In acetonitrile; at 120℃; for 24h;Sealed tube; | General procedure: The mixture of azobenzenes 1 (0.25 mmol), alcohols 2(0.5 mmol), TBHP (1 mmol) and CH3CN (1 mL) were added into a sealed tube under air. After being stirred vigorously at 120 C for 24 h, the mixture was evaporated under vacuum. The corresponding product was isolated by silica gel column chromatography with a petroleum ether/ethyl acetate mixture as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: To a solution of 1,2,3,4-<strong>[4049-33-6]tetra-O-acetyl-β-D-xylopyranose</strong> 1 (1.0 equiv) and the corresponding alcohol (1.2 equiv, ethyl glycolate, methyl 6-hydroxyhexanoate or methyl 4-(hydroxymethyl)benzoate) in CH2Cl2 was added BF3.Et2O (1.5 equiv) at 0C under Ar. After stirring for 2h, at room temperature, the organic mixture was washed with a saturated solution of NaHCO3 and water, dried over Na2SO4 and concentrated to dryness under reduced pressure. To a solution of the previously xyloside obtained in MeOH was added Na (10.0mol %) under Ar. After stirring for 1h at room temperature, the mixture was neutralized with DOWEX (H+), filtered and concentrated to dryness under reduced pressure. Xyloside 2 was obtained as a white solid and was characterized without any further purification. The xyloside 3 was purified by flash chromatography over silica gel with eluting mixture CH2Cl2/MeOH: 8:2 to afford a white solid. In the case of xyloside 4, the residue was washed with CH2Cl2 (3×50mL) to afford a pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetramethylammonium bromide; cesium fluoride In N,N,N,N,N,N-hexamethylphosphoric triamide; N,N-dimethyl acetamide at 70℃; for 26h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 4-(methoxycarbonyl)benzyl alcohol With pyridine; diphenyl phosphite In dichloromethane at -40 - 20℃; for 2.16667h; Inert atmosphere; Stage #2: 9-Fluorenylmethanol In dichloromethane at 20℃; Inert atmosphere; | H-Phosphonates 3a-g, 11, 14, and 17. General procedure: A round bottom flask was equipped with a magnetic stir bar, 1 equivalent of the ethyl benzoate 4a-4e and charged with argon(g). Freshly distilled room temperature dichloromethane was added to yield a 0.2 M solution of the dissolved ethyl benzoate, solution A. In a separate round bottom flask was added 2 equivalents of diphenylphosphite and freshly distilled pyridine to yield a 1.6 M solution of diphenylphosphite, solution B. Solution B was then chilled to -40 oC for 30 minutes. Solution A was added dropwise to solution B over 10 min. once the addition was completed, the reaction flask was allowed to stir at room temperature under argon(g) for 2 h. 4 equivalents of solid (9H-fluoren-9-yl)methanol was then added in one portion to the reaction flask and allowed to stir at room temperature overnight under argon(g). The crude reaction mixture was then diluted with ethyl acetate (five-times the volume of dichloromethane in the reaction) and washed thrice with 1 N HCl, once with milliQ water, and washed with saturated sodium bicarbonate until the pH reached 8-9. The organic layer was then dried over magnesium sulfate, concentrated under vacuum, and chromatographed on silica gel. Compounds were purified in a general gradient of 100% dichloromethane until full elution of excess (9H-fluoren-9-yl)methanol afterwards the mobile phase was switched to mixtures of acetonitrile and dichloromethane ranging from 5-25% acetonitrile with the exception of compound 14 and 17. Compound 14 which was carried on to the next step, Atherton Todd reaction, purification. Compound 17 crystallized from ethyl acetate and hexanes (1 gram of crude material ~1mL dichloromethane : 20 mL hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1) Methyl 4-(hydroxymethyl)benzoate (37 mg) and cyanomethylenetributylphosphorane (0.12 mL) were added to a solution of the compound (50 mg) obtained in Reference Example 1-1 in toluene (1.5 mL), and the mixture was stirred under a nitrogen atmosphere at 100C for 2 hours. The reaction solution was cooled, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1 to 1:2) to give methyl 4-[[6-[2-(2-oxanyl)-3-pyrazolyl]-3-pyridinyl]oxymethyl]benzoate (69 mg) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 56% 2: 15 %Chromat. 3: 6 %Chromat. 4: 5 %Chromat. | With hydrogen sulfide In Hexadecane; toluene at 180℃; for 18h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With copper (II) acetate In toluene at 110℃; | General procedure for the synthesis of cinnamates or cinnamamides General procedure: 0.7mmol of the corresponding cyclopropenone were inserted in a glass vialwith either Cu(OAc)2 (1-2 mol%) or NiCuMOF (10 mol%), toluene (0.5M final dilution respect to the cyclopropenone reactant) and the correspondingalcohol or amine (0.35 mmol). The solution was left overnightat 100 C and at the end was quenched with water (5 ml). Then, themixture was extracted with EtOAc (3 × 5 ml) and the organic layerswere washed with water (5 ml) and brine (5 ml). Afterwards, the organicphase was dried over MgSO4, filtered and concentrated under vacuum.The resulting mixture was purified by either thin-layer chromatography(TLC) or flash chromatography with the appropriate AcOEt/n-hexanesmixture. |
Tags: 6908-41-4 synthesis path| 6908-41-4 SDS| 6908-41-4 COA| 6908-41-4 purity| 6908-41-4 application| 6908-41-4 NMR| 6908-41-4 COA| 6908-41-4 structure
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